Fused pyrazine derivatives as a2a / a2b inhibitors

ABSTRACT

This application relates to compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, which modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors, and are useful in the treatment of diseases related to the activity of adenosine receptors including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.

TECHNICAL FIELD

The present invention provides fused pyrazine derivatives that modulatethe activity of adenosine receptors, such as subtypes A2A and A2B, andare useful in the treatment of diseases related to the activity ofadenosine receptors including, for example, cancer, inflammatorydiseases, cardiovascular diseases, and neurodegenerative diseases.

BACKGROUND

Adenosine is an extracellular signaling molecule that can modulateimmune responses through many immune cell types. Adenosine was firstrecognized as a physiologic regulator of coronary vascular tone by Druryand Szent-Györgyu (Sachdeva, S. and Gupta, M. Saudi PharmaceuticalJournal, 2013, 21, 245-253), however it was not until 1970 that Sattinand Rall showed that adenosine regulates cell function via occupancy ofspecific receptors on the cell surface (Sattin, A., and Rall, T. W.,1970. Mol. Pharmacol. 6, 13-23; Hasko', G., at al., 2007, Pharmacol.Ther. 113, 264-275).

Adenosine plays a vital role in various other physiological functions.It is involved in the synthesis of nucleic acids, when linked to threephosphate groups; it forms ATP, the integral component of the cellularenergy system. Adenosine can be generated by the enzymatic breakdown ofextracellular ATP, or can be also released from injured neurons andglial cells by passing the damaged plasma membrane (Tautenhahn, M. etal. Neuropharmacology, 2012, 62, 1756-1766). Adenosine produces variouspharmacological effects, both in periphery and in the central nervoussystem, through an action on specific receptors localized on cellmembranes (Matsumoto, T. et al. Pharmacol. Res., 2012, 65, 81-90).Alternative pathways for extracellular adenosine generation have beendescribed. These pathways include the production of adenosine fromnicotinamide dinucleotide (NAD) instead of ATP by the concerted actionof CD38, CD203a and CD73. CD73-independent production of adenosine canalso occur by other phosphates such as alkaline phosphatase orprostate-specific phosphatase.

There are four known subtypes of adenosine receptor in humans includingA1, A2A, A2B and A3 receptors. A1 and A2A are high affinity receptors,whereas A2B and A3 are low affinity receptors. Adenosine and itsagonists can act via one or more of these receptors and can modulate theactivity of adenylate cyclase, the enzyme responsible for increasingcyclic AMP (cAMP). The different receptors have differential stimulatoryand inhibitory effects on this enzyme. Increased intracellularconcentrations of cAMP can suppress the activity of immune andinflammatory cells (Livingston, M. et al., Inflamm. Res., 2004, 53,171-178).

The A2A adenosine receptor can signal in the periphery and the CNS, withagonists explored as anti-inflammatory drugs and antagonists exploredfor neurodegenerative diseases (Carlsson, J. et al., J. Med. Chem.,2010, 53, 3748-3755). In most cell types the A2A subtype inhibitsintracellular calcium levels whereas the A2B potentiates them. The A2Areceptor generally appears to inhibit inflammatory response from immunecells (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

A2B receptors are highly expressed in the gastrointestinal tract,bladder, lung and on mast cells (Antonioli, L. et al., Nature ReviewsCancer, 2013, 13, 842-857). The A2B receptor, although structurallyclosely related to the A2A receptor and able to activate adenylatecyclase, is functionally different. It has been postulated that thissubtype may utilize signal transduction systems other than adenylatecyclase (Livingston, M. et al., Inflamm. Res., 2004, 53, 171-178). Amongall the adenosine receptors, the A2B adenosine receptor is a lowaffinity receptor that is thought to remain silent under physiologicalconditions and to be activated in consequence of increased extracellularadenosine levels (Ryzhov, S. et al. Neoplasia, 2008, 10, 987-995).Activation of A2B adenosine receptor can stimulate adenylate cyclase andphospholipase C through activation of Gs and Gq proteins, respectively.Coupling to mitogen activated protein kinases has also been described(Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

In the immune system, engagement of adenosine signaling can be acritical regulatory mechanism that protects tissues against excessiveimmune reactions. Adenosine can negatively modulate immune responsesthrough many immune cell types, including T-cells, natural-killer cells,macrophages, dendritic cells, mast cells and myeloid-derived suppressorcells (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29,7-16).

In tumors, this pathway is hijacked by tumor micro-environments andsabotages the antitumor capacity of immune system, promoting cancerprogression. In the tumor micro-environment, adenosine was mainlygenerated from extracellular ATP by CD39 and CD73. Multiple cell typescan generate adenosine by expressing CD39 and CD73. This is the case fortumor cells, T-effector cells, T-regulatory cells, tumor associatedmacrophages, myeloid derived suppressive cells (MDSCs), endothelialcells, cancer-associated fibroblast (CAFs) and mesenchymal stromal/stemcells (MSCs). Hypoxia, inflammation and other immune-suppressivesignaling in tumor micro-environment can induce expression of CD39, CD73and subsequent adenosine production. As a result, adenosine level insolid tumors is unusually high compared to normal physiologicalconditions.

A2A are mostly expressed on lymphoid-derived cells, including T-effectorcells, T regulatory cells and nature killing cells. Blocking A2Areceptor can prevent downstream immunosuppressive signals thattemporarily inactivate T cells. A2B receptors are mainly expressed onmonocyte-derived cells including dendritic cells, tumor-associatedmacrophages, myeloid derived suppressive cells (MDSCs), and mesenchymalstromal/stem cells (MSCs). Blocking A2B receptor in preclinical modelscan suppress tumor growth, block metastasis, and increase thepresentation of tumor antigens.

In terms of safety profile of ADORA2A/ADORA2B (A2A/A2B) blockage, theA2A and A2B receptor knockout mice are all viable, showing no growthabnormalities and are fertile (Allard, B. et al. Current Opinion inPharmacology, 2016, 29, 7-16). A2A KO mice displayed increased levels ofpro-inflammatory cytokines only upon challenge with LPS and no evidenceof inflammation at baseline (Antonioli, L. et al., Nature ReviewsCancer, 2013, 13, 842-857). A2B KO mice exhibited normal platelet, redblood, and white cell counts but increased inflammation at baseline(TNF-alpha, IL-6) in naive A2B KO mice (Antonioli, L. et al., NatureReviews Cancer, 2013, 13, 842-857). Exaggerated production of TNF-alphaand IL-6 was detected following LPS treatment. A2B KO mice alsoexhibited increased vascular adhesion molecules that mediateinflammation as well leukocyte adhesion/rolling; enhanced mast-cellactivation; increased sensitivity to IgE-mediated anaphylaxis andincreased vascular leakage and neutrophil influx under hypoxia(Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857).

In summary, there is a need to develop new adenosine receptor selectiveligands, such as for subtypes A2A and A2B, for the treatment of diseasessuch as cancer, inflammatory diseases, cardiovascular diseases andneurodegenerative diseases. This application is directed to this needand others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting an activityof an adenosine receptor, comprising contacting the receptor with acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ora disorder associated with abnormal expression of adenosine receptors,comprising administering to said patient a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION Compounds

The present application provides, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl of R¹ are each optionally substituted with 1, 2, 3,or 4 independently selected R^(1A) substituents;

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl ofR^(a1), R^(b1), R^(c1), and R^(d1) are each optionally substituted with1, 2, 3, or 4 independently selected R^(1A) substituents;

each R^(e1) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(1A) is independently selected from OH, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

X³ is N or CR³;

R³ is selected from H, D, halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, amino,C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)amino sulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino; Cy¹ is selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy¹ are eachoptionally substituted with 1, 2, 3, 4, 5, or 6 independently selectedR⁷ substituents;

each R⁷ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a7), SR^(a7), NHOR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)NR^(c7)(OR^(a7)), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7),C(═NOH)R^(b7), C(═NCN)R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NOH)NR^(c7)R^(d7),NR^(c7)C(═NCN)NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))R^(b7),NR^(c7)S(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)(═NR^(e7))R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7),OS(O)(═NR^(e7))R^(b7), OS(O)₂R^(b7), SF₅, P(O)R^(f7)R^(g7),OP(O)(OR^(h7))(OR^(i7)), P(O)(OR^(h7))(OR^(i7)), and BR^(j7)R^(k7),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁷ are each optionally substituted with 1, 2, 3, or 4independently selected R^(7A) substituents;

each R^(a7), R^(b7), R^(c7), and R^(d7) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a7), R^(b7), R^(c7)and R^(d7) are each optionally substituted with 1, 2, 3, or 4independently selected R^(7A) substituents;

or, any R^(c7) and R^(d7), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(7A) substituents;

each R^(e7) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f) and R^(g7) is independently selected from H, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h7) and R^(i7) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j7) and R^(k7) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j7) and R^(k7) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(7A) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)amino sulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a2), SR^(a2),NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOH)R^(b2),C(═NCN)R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NOH)NR^(c2)R^(d2),NR^(c2)C(═NCN)NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅, P(O)R^(f2)R^(g2),OP(O)(OR^(h2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), and BR^(j2)R^(k2),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R² are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(2A) substituents;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4)SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOH)R^(b4),C(═NCN)R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NOH)NR^(c4)R^(d4),NR^(c4)C(═NCN)NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), SF₅, P(O)R^(f4)R^(g4),OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(4A) substituents;

provided that:

-   -   (a) when R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl and 4-10 membered heterocycloalkyl, wherein        the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and        4-10 membered heterocycloalkyl of R² are each optionally        substituted with 1, 2, 3, 4, 5, or 6 independently selected        R^(2A) substituents;        -   then R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀            cycloalkyl, 5-10 membered heteroaryl, 4-10 membered            heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀            cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆            alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN,            NO₂, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4),            C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4),            OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),            NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),            NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOH)R^(b4),            C(═NCN)R^(b4), C(═NR^(e4))NR^(c4)R^(d4),            NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),            NR^(c4)C(═NOH)NR^(c4)R^(d4), NR^(c4)C(═NCN)NR^(c4)R^(d4),            NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)NR^(c4)R^(d4),            NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),            NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),            S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),            S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4),            SF₅, P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)),            P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4), wherein the C₁₋₆            alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀            cycloalkyl, 5-10 membered heteroaryl, 4-10 membered            heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀            cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆            alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of            R⁴ are each optionally substituted with 1, 2, 3, 4, 5, or 6            independently selected R^(4A) substituents;            or, alternatively,    -   (b) when R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂,        OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),        C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        C(═NR^(e2))R^(b2), C(═NOH)R^(b2), C(═NCN)R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NOH)NR^(c2)R^(d2), NR^(c2)C(═NCN)NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))R^(b2), NR^(c2)S(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR²R^(d2) S(O)R^(b2),        S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),        OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅, P(O)R^(f2)R^(g2),        OP(O)(OR)(OR^(i2)), P(O)(OR^(h))(OR^(i2)), and BR^(j2)R^(k2),        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally        substituted with 1, 2, 3, 4, 5, or 6 independently selected        R^(2A) substituents;        -   then R⁴ is selected from D, halo, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆            alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered            heteroaryl)-C₁₋₆ alkyl-, (4-10 membered            heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),            NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),            C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4), OC(O)R^(b4),            OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4),            NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),            NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOH)R^(b4),            C(═NCN)R^(b4), C(═NR^(e4))NR^(c4)R^(d4),            NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),            NR^(c4)C(═NOH)NR^(c4)R^(d4), NR^(c4)C(═NCN)NR^(c4)R^(d4),            NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)NR^(c4)R^(d4),            NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),            NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),            S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),            S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4),            SF₅, P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)),            P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4), wherein the C₁₋₆            alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,            C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered            heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered            heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally            substituted with 1, 2, 3, 4, 5, or 6 independently selected            R^(4A) substituents;

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a2), R^(b2), R^(c2)and R^(d2) are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(2A) substituents;

or, any R^(c2) and R^(d2), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R^(2A) substituents;

each R^(e2) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f2) and R^(g2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h2) and R^(i2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j2) and R^(k2) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j2) and R^(k2) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NOH)R^(b21), C(═NCN)R^(b21),C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NOH)NR^(c21)R^(d21), NR^(c21)C(═NCN)NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))R^(b21), NR^(c21)S(O)NR^(c21)R^(d21),NR^(c21)S(O)R^(b21), NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)(═NR^(e21))R^(b21)NR^(c21) S(O)₂NR^(c21)R^(d21), S(O)R^(b21),S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), OS(O)₂R^(b21), SF₅, P(O)R^(f21)R^(g21),OP(O)(OR^(h21))(OR^(i21)), P(O)(OR^(h21))(OR^(i21)), andBR^(j21)R^(k21), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents;

each R^(a21), R^(b21), R^(c21) and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21),R^(c21) and R^(d21) are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

or, any R^(c21) and R^(d21), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

each R^(e21) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f21) and R^(g21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h21) and R^(i21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j21) and R^(k21) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j21) and R^(k21) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2B) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22),C(O)NR^(c22)R^(d22), C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22) OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═N^(e22))R^(b22), C(═NOH)R^(b22),C(═NCN)R^(b22)C(═NR^(e22))NR²²R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NOH)NR^(c22)R^(d22),NR^(c22)C(═NCN)NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), OS(O)₂R^(b22), SF₅, P(O)R^(f22)R^(g22),OP(O)(OR^(h22))(OR^(i22)), P(O)(OR^(h22))(OR^(i22)), andBR^(j22)R^(k22), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2C) substituents;

each R^(a22), R^(b22), R^(c22) and R^(d22) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(b22),R^(c22) and R^(d22) are each optionally substituted with 1, 2, 3, or 4independently selected R²C substituents;

or, any R^(c22) and R^(d22), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R²C substituents;

each R^(e22) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f22) and R^(g22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h22) and R^(i22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(j22) and R^(k22) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j22) and R^(k22) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R²C is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)amino sulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(b4), R^(c4)and R^(d4) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4A) substituents;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R^(4A) substituents;

each R^(e4) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f4) and R^(g4) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h4) and R^(i4) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j4) and R^(k4) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j4) and R^(k4) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41) OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NOH)R^(b41),C(═NCN)R^(b41)C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NOH)NR^(c41)R^(d41),NR^(c41)C(═NCN)NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41)NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), OS(O)₂R^(b41), SF₅, P(O)R^(f41)R^(g41),OP(O)(OR^(h41))(OR^(i41)), P(O)(OR^(h41))(OR^(i41)), andBR^(j41)R^(k41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents;

each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(b41),R^(c41) and R^(d41) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents;

or, any R^(c41) and R^(d41), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R^(4B) substituents;

each R^(e41) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f41) and R^(g41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h41) and R⁴¹ is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(j41) and R^(k41) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy;

or any R^(j41) and R^(k41) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(4B) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42) OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),C(═NR^(e42))R^(b42), C(═NOH)R^(b42), C(═NCN)R^(b42),C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NOH)NR^(c42)R^(d42), NR^(c42)C(═NCN)NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))R^(b42), NR^(c42)S(O)NR^(c42)R^(d42),NR^(c42)S(O)R^(b42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), OS(O)₂R^(b42), SF₅, P(O)R^(f42)R^(g42),OP(O)(OR^(h42))(OR^(i42)), P(O)(OR^(h42))(OR^(i42)), andBR^(j42)R^(k42), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents;

each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(b42),R^(c42) and R^(d42) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4C) substituents;

or, any R^(c42) and R^(d42), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4C) substituents;

each R^(e42) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f42) and R^(g42) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h42) and R^(i42) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂-6 alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j42) and R^(k42) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j42) and R^(k42) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(4C) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a43), SR^(a43), NHOR^(a43), C(O)R^(b43),C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)), C(O)OR^(a43), OC(O)R^(b43),OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43), NR^(c43)NR^(c43)R^(d43),NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43), NR^(c43)C(O)NR^(c43)R^(d43),C(═NR^(e43))R^(b43), C(═NOH)R^(b43), C(═NCN)R^(b43),C(═NR^(e43))NR^(c43)R^(d43), NR^(c43)C(═NR^(e43))NR^(c43)R^(d43),NR^(c43)C(═NOH)NR^(c43)R^(d43), NR^(c43)C(═NCN)NR^(c43)R^(d43),NR^(c43)C(═NR^(e43))R^(b43), NR^(c43) S(O)NR^(c43)R^(d43), NR^(c43)S(O)R^(b43), NR^(c43) S(O)₂R^(b43), NR^(c43) S(O)(═NR^(e43))R^(b43),NR^(c43) S(O)₂NR^(c43)R^(d43), S(O)R^(b43), S(O)NR^(c43)R^(d43),S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43), OS(O)(═NR^(e43))R^(b43),OS(O)₂R^(b43), SF₅, P(O)R^(f43)R^(g43), OP(O)(OR^(h43))(OR^(i43)),P(O)(OR^(h43))(OR^(i43)), and BR^(j43)R^(k43), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4C) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4D)substituents;

each R^(a43), R^(b43), R^(c43) and R^(d43) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a43), R^(b43),R^(c43) and R^(d43) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents;

or, any R^(c43) and R^(d43), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents;

each R^(e43) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f43) and R^(g43) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h43) and R^(i43) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j43) and R^(k43) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j43) and R^(k43) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(4D) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-7membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a44), SR^(a44),NHOR^(a44), C(O)R^(b44), C(O)NR^(c44)R^(d44), C(O)NR^(c44)(OR^(a44)),C(O)OR^(a44), OC(O)R^(b44), OC(O)NR^(c44)R^(d44), NR^(c44)R^(d44),NR^(c44)NR^(c44)R^(d44), NR^(c44)C(O)R^(b44), NR^(c44)C(O)OR^(a44),NR^(c44)C(O)NR^(c44)R^(d44), C(═NR^(e44))R^(b44), C(═NOH)R^(b44),C(═NCN)R^(b44), C(═NR^(e44))NR^(c44)R^(d4) ₄,NR^(c44)C(═NR^(e44))NR⁴⁴R^(d44), NR^(c44)C(═NOH)NR^(c44)R^(d44),NR^(c44)C(═NCN)NR^(c44)R^(d44), NR^(c44)C(═NR^(e44))R^(b44),NR^(c44)S(O)NR^(c44)R^(d44), NR^(c44)S(O)R^(b44), NR^(c44)S(O)₂R^(b44),NR^(c44)S(O)(═NR^(e44))R^(b44), NR^(c44)S(O)₂NR^(c44)R^(d44),S(O)R^(b44), S(O)NR^(c44)R^(d44), S(O)₂R^(b44), S(O)₂NR^(c44)R^(d44),OS(O)(═NR^(e44))R^(b44), OS(O)₂R^(b44), SF₅, P(O)R^(f44)R^(g44),OP(O)(OR^(h44))(OR^(i44)), P(O)(OR^(h44))(OR^(i44)), and BR⁴⁴R^(k44),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(4D) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4E) substituents;

each R^(a44), R^(b44), R^(c44) and R^(d44) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-7 membered heteroaryl, 4-10 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a44), R^(b44), R^(c44) and R^(d44) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4E) substituents;

or, any R^(c44) and R^(d44), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4E) substituents;

each R^(e44) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f44) and R^(g44) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-7 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h44) and R^(i44) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-7membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j44) and R^(k44) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j44) and R^(k44) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;and

each R^(4E) is independently selected from OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)amino sulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of any “alkyl”, “alkenyl”, “alkynyl”, “aryl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₆alkyl-”, “alkylene”, “alkenylene”, and “alkynylene” linking groups, areeach optionally replaced by a deuterium atom.

In some embodiments, the compound of Formula (I) provided herein, or apharmaceutically acceptable salt thereof, is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formulas (I) and (II), R¹ is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl of R¹ areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(1A) substituents.

In some embodiments of Formulas (I) and (II), R¹ is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments of Formulas (I) and (II), R¹ is H or C₁₋₃ alkyl.

In some embodiments of Formulas (I) and (II), R¹ is H.

In some embodiments of Formulas (I) and (II), R³ is selected from H, D,halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl,C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, amino, C₁₋₃ alkylamino, di(C₁₋₃alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.

In some embodiments of Formulas (I) and (II), R³ is selected from H, D,halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl.

In some embodiments of Formulas (I) and (II), R³ is CN or H.

In some embodiments of Formulas (I) and (II), R³ is H.

In some embodiments of Formulas (I) and (II), R² is selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,OR^(a2), SR^(a2), C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, and C₆₋₁₀ aryl-C₁₋₆ alkyl-,wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, and C₆₋₁₀ aryl-C₁₋₆ alkyl-, of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents.

In some embodiments of Formulas (I) and (II), R² is selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents.

In some embodiments of Formulas (I) and (II), each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21).

In some embodiments of Formulas (I) and (II), each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21).

In some embodiments of Formulas (I) and (II), each R^(a21), R^(b21),R^(c21), and R^(d21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21) and R^(d21)are each optionally substituted with 1 or 2 independently selectedR^(2B) substituents.

In some embodiments of Formulas (I) and (II), each R^(a21), R^(b21),R^(c21), and R^(d21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments of Formulas (I) and (II), R² is selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; and

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR¹, NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21).

In some embodiments of Formulas (I) and (II), R² is selected from C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl of R² are each optionally substituted with 1 or 2independently selected R^(2A) substituents.

In some embodiments of Formulas (I) and (II), each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21)and S(O)R^(b21).

In some embodiments of Formulas (I) and (II), each R^(a21), R^(b21),R^(c21), and R^(d21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments of Formulas (I) and (II), R² is selected from C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl of R² are each optionally substituted with 1 or 2independently selected R^(2A) substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21); and

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl.

In some embodiments of Formulas (I) and (II), R² is selected fromcyclopropyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl,and pyridinonyl, each of which is optionally substituted with 1 or 2independently selected R^(2A) substituents.

In some embodiments of Formulas (I) and (II), each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21),C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)C(O)R^(b21),NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21), and S(O)R^(b21).

In some embodiments of Formulas (I) and (II), each R^(a21), R^(b21),R^(c21), and R^(d21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R² is selected fromcyclopropyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyridin-(2H)-yl,and pyridinonyl, each of which is optionally substituted with 1 or 2independently selected R^(2A) substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21); and

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R² is selected fromphenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl, wherein the phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl of R² are each optionallysubstituted with 1, 2, or 3 independently selected R^(2A) substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a21),SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21), wherein said phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl of R^(2A) areoptionally substituted with 1, 2, or 3 independently selected R^(2B)substitutents;

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(2B) is independently selected from halo, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments of Formulas (I) and (II), R² is selected from C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl of R² are each optionally substituted with 1 or 2independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, and C(O)NR^(c21)R^(d21), wherein said C₁₋₄ alkyl of R^(2A) isoptionally substituted with 1, 2, or 3 independently selected R^(2B)substitutents;

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(2B) is independently selected from halo and OH.

In some embodiments of Formulas (I) and (II), R² is selected fromcyclopropyl, oxazolyl, triazolyl, pyrazolyl, pyridyl, pyrimidinyl,dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionallysubstituted with 1 or 2 independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21), wherein said C₁₋₆ alkyl of R^(2A) is optionallysubstituted with 1, 2, or 3 independently selected R^(2B) substituents;

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R^(2B) is independently selected from halo and OH.

In some embodiments of Formulas (I) and (II), R² is selected from1-(trifluoromethyl)cycloprop-1-yl, 1-ethyl-1H-pyrazol-5-yl,1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl,pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, pyridin-4-yl,4-(1-hydroxyethyl)-2-methyloxazol-5-yl,2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl,1-ethyl-1H-1,2,3-triazol-5-yl, and 1-methyl-1H-1,2,3-triazol-5-yl.

In some embodiments of Formulas (I) and (II), R² is selected from1-(trifluoromethyl)cycloprop-1-yl, 1-ethyl-1H-pyrazol-5-yl,1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl,pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, pyridin-4-yl,4-(1-hydroxyethyl)-2-methyloxazol-5-yl,2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl,1-ethyl-1H-1,2,3-triazol-5-yl, and 1-methyl-1H-1,2,3-triazol-5-yl.

In some embodiments of Formulas (I) and (II), R² is selected from1-(trifluoromethyl)cycloprop-1-yl, 1-ethyl-1H-pyrazol-5-yl,1-propyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl,pyrimidin-4-yl, 3,6-dihydropyridin-4-yl-1(2H)-carboxamide, andpyridin-4-yl.

In some embodiments of Formulas (I) and (II), R⁴ is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR⁴R^(d4), S(O)R^(b4), and S(O)₂R^(b4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1, 2, 3, or 4independently selected R^(4A) substituents.

In some embodiments of Formulas (I) and (II), each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a41), SR^(a41),NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41)OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), S(O)R^(b41), andS(O)₂R^(b41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, of R^(4A) are each optionally substituted with 1, 2,3, or 4 independently selected R^(4B) substituents.

In some embodiments of Formulas (I) and (II), each R^(4B) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments of Formulas (I) and (II), each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a41), SR^(a41),NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41)OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), S(O)R^(b41), andS(O)₂R^(b41).

In some embodiments of Formulas (I) and (II), R⁴ is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR⁴R^(d4), S(O)R^(b4), and S(O)₂R^(b4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1, 2, 3, or 4independently selected R^(4A) substituents; and

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41).

In some embodiments of Formulas (I) and (II), R⁴ is selected from H, D,halo, C₁-6 alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,5-6 membered heteroaryl, phenyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), and NR^(c4)C(O)NR^(c4)R^(d4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, 5-6 memberedheteroaryl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1 or 2 independentlyselected R^(4A) substituents.

In some embodiments of Formulas (I) and (II), each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, and OR^(a41).

In some embodiments of Formulas (I) and (II), each R^(a4), R^(b4),R^(c4), and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), each R^(a41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.

In some embodiments, any R^(c4) and R^(d4), attached to the same N atom,together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group, wherein the 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4A) substituents.

In some embodiments, any R^(c4) and R^(d4), attached to the same N atom,together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group, wherein the 4-10 memberedheterocycloalkyl group is optionally substituted with 1 or 2independently selected R^(4A) substituents.

In some embodiments of Formulas (I) and (II), R⁴ is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,5-6 membered heteroaryl, phenyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), and NR^(c4)C(O)NR^(c4)R^(d4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, 5-6 memberedheteroaryl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1 or 2 independentlyselected R^(4A) substituents;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, andOR^(a41);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R^(a41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R⁴ is selected from C₁₋₆alkyl, phenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-,C(O)NR⁴R^(d4), and NR^(c4)C(O)OR^(a4), wherein the C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆ alkyl- of R⁴ areeach optionally substituted with 1 or 2 independently selected R^(4A)substituents;

In some embodiments of Formulas (I) and (II), each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, and OR^(a41).

In some embodiments of Formulas (I) and (II), each R^(a4), R^(c4), andR^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-6 memberedheterocycloalkyl group.

In some embodiments of Formulas (I) and (II), each R^(a41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R⁴ is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4), andS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said C₁₋₆ alkyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R^(a4), R^(b4), R^(c4), and R^(d4) are eachoptionally substituted by 1, 2, or 3 independently selected R^(4A)substituents;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a41),SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41),OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl of R^(4A) are each optionally substituted by 1or 2 independently selected R^(4B) substituents;

each R^(a41), R^(b41), R^(c41), and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl ofR^(a41), R^(b41), R^(c41), and R^(d41) is optionally substituted by 1,2, or 3 independently selected R^(4B) substituents; and

each R^(4B) is independently selected from halo, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromphenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₃ alkyl-, C(O)R^(b4), C(O)NR⁴R^(d4), andNR⁴R^(d4), wherein the phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₃ alkyl- of R⁴ are eachoptionally substituted with 1 or 2 independently selected R^(4A)substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, phenyl, and 4-7 membered heterocycloalkyl, wherein saidC₁₋₆ alkyl, phenyl, and 4-7 membered heterocycloalkyl of R^(a4), R^(b4),R^(c4), and R^(d4) are optionally substituted with 1, 2, or 3independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, 4-7 memberedheterocycloalkyl, and OH, wherein said 4-7 membered heterocycloalkyl ofR^(4A) is optionally substituted with 1 or 2 independently selectedR^(4B) substituents; and

each R^(4B) is independently selected from halo, OH, and C₁₋₄ alkyl

In some embodiments of Formulas (I) and (II), R⁴ is selected fromphenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-,C(O)NR⁴R^(d4), and NR^(c4)C(O)OR^(a4), wherein the C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆ alkyl- of R⁴ areeach optionally substituted with 1 or 2 independently selected R^(4A)substituents;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, andOR^(a41);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-6 memberedheterocycloalkyl group; and

each R^(a41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromC(O)NHC₁₋₆alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl,C(O)N(C₁₋₆ alkyl)₂, NHC(O)OC₁₋₆ alkyl, (azetidinyl)-C₂₋₆ alkyl,(pyridyl)-C₁₋₆ alkyl, (phenyl)-C₁₋₆ alkyl, (fluorophenyl)-C₁₋₆ alkyl,3,6-dihydro-2H-pyranyl, NH-(phenyl), and pyridyl.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromC(O)NHC₁₋₆alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl,C(O)N(C₁₋₆ alkyl)₂, NHC(O)OC₁₋₆ alkyl, (azetidinyl)-C₁₋₆ alkyl,(pyridyl)-C₁₋₆ alkyl, (phenyl)-C₁₋₆ alkyl, (fluorophenyl)-C₁₋₆ alkyl,3,6-dihydro-2H-pyranyl, NH-(phenyl), pyridyl, and(pyrrolo[3,2-b]pyridinyl)-C₁₋₆ alkyl,

wherein each C₁₋₆ alkyl and azetidinyl group is optionally substitutedby 1 or 2 OH groups; and each pyridyl is optionally substituted by amethylpiperazinyl group.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromC(O)NHC₁₋₆alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl, C(O)-piperidinyl,C(O)N(C₁₋₆ alkyl)₂, NHC(O)OC₁₋₆ alkyl, (azetidinyl)-C₁₋₆ alkyl,(pyridyl)-C₁₋₆ alkyl, (phenyl)-C₁₋₆ alkyl, (fluorophenyl)-C₁₋₆ alkyl,3,6-dihydro-2H-pyranyl, NH-(phenyl), and pyridyl,

wherein each C₁₋₆ alkyl and azetidinyl group is optionally substitutedby 1 or 2 OH groups; and each pyridyl is optionally substituted by amethylpiperazinyl group.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromC(O)NHCH₂CH₃, C(O)N(CH₃)(CH₂CH₃), C(O)N(CH₂CH₃)₂, NHC(O)OCH₂CH₃,C(O)-azetidinyl, C(O)-hydroxyazetidinyl, C(O)-pyrrolidinyl,C(O)-piperidinyl, CH₂-azetidinyl, CH₂-pyridyl, CH₂-fluorophenyl,CH(OH)-flurophenyl, NH-phenyl, 3,6-dihydro-2H-pyranyl,(methylpiperazinyl)pyridinyl, and (1H-pyrrolo[3,2-b]pyridin-3-yl)methyl

In some embodiments of Formulas (I) and (II), R⁴ is selected fromC(O)NHCH₂CH₃, C(O)N(CH₃)(CH₂CH₃), C(O)N(CH₂CH₃)₂, NHC(O)OCH₂CH₃,C(O)-azetidinyl, C(O)-hydroxyazetidinyl, C(O)-pyrrolidinyl,C(O)-piperidinyl, CH₂-azetidinyl, CH₂-pyridyl, CH₂-fluorophenyl,CH(OH)-flurophenyl, NH-phenyl, 3,6-dihydro-2H-pyranyl, and(methylpiperazinyl)pyridinyl.

In some embodiments of Formulas (I) and (II), R² is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), S(O)R^(b2), andS(O)₂R^(b2).

In some embodiments of Formulas (I) and (II), each R^(a2), R^(b2),R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R² is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), S(O)R^(b2), andS(O)₂R^(b2); and

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (II), R² is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and CN.

In some embodiments of Formulas (I) and (II), R² is selected from H,difluoroethyl, bromo, and CN.

In some embodiments of Formulas (I) and (II), R⁴ is selected from C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4) andS(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents.

In some embodiments of Formulas (I) and (II), each R^(a4), R^(c4), andR^(d4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a41), SR^(a41),NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41),OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41).

In some embodiments of Formulas (I) and (II), R⁴ is selected from C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4) andS(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected from Hand C₁₋₆ alkyl; and

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41).

In some embodiments of Formulas (I) and (II), R⁴ is selected fromphenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-,C(O)NR^(c4)R^(d4), and NR^(c4)C(O)OR^(a4), wherein each C₁₋₆ alkyl isoptionally substituted by 1 or 2 OH groups; and the phenyl-C₁₋₆ alkyl-is optionally substituted with 1 or 2 independently selected halogroups.

In some embodiments of Formulas (I) and (II), each R^(a4), R^(b4),R^(c4), and R^(d4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), each R⁴ is selected fromphenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, andC(O)NR⁴R^(d4), wherein the phenyl-C₁₋₆ alkyl- and (5-6 memberedheteroaryl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with 1 or2 substituents independently selected from OH and halo; and

each R^(a4), R^(c4), and R^(d4) is independently selected from H andC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromphenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-,C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), wherein each C₁₋₆ alkyl isoptionally substituted by 1 or 2 OH groups; and the phenyl-C₁₋₆ alkyl-is optionally substituted with 1 or 2 independently selected halogroups; and

each R^(a4), R^(c4), and R^(d4) is independently selected from H andC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), R⁴ is selected fromC(O)NHCH₂CH₃, —CH₂-pyridyl, CH₂-fluorophenyl, and CH(OH)-fluorophenyl.

In some embodiments of Formula (II), R² is selected from H, D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁-6 alkyl-, CN, NO₂, OR^(a2), SR^(a2), NHOR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NOH)R^(b2), C(═NCN)R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NOH)NR^(c2)R^(d2), NR^(c2)C(═NCN)NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)(═NR^(e2))R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅,P(O)R^(f2)R^(g2), OP(O)(OR^(b2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), andBR^(j2)R^(k2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(2A) substituents; and

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4)SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOH)R^(b4),C(═NCN)R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NOH)NR^(c4)R^(d4),NR^(c4)C(═NCN)NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4)NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), SF₅, P(O)R^(f4)R^(g4),OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(4A) substituents.

In some embodiments of Formulas (I) and (II), Cy¹ is C₆₋₁₀ aryl which isoptionally substituted by 1, 2, 3, or 4 independently selected R⁷substituents.

In some embodiments of Formulas (I) and (II), Cy¹ is phenyl which isoptionally substituted by 1 or 2 independently selected R⁷ substituents.

In some embodiments of Formulas (I) and (II), each R⁷ is independentlyselected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (II), Cy¹ is phenyl which isoptionally substituted by 1 or 2 independently selected R⁷ substituents;and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (II), Cy¹ is phenyl which issubstituted by 1 or 2 independently selected R⁷ substituents; and

each R⁷ is independently selected from halo and CN.

In some embodiments of Formulas (I) and (II), Cy¹ is unsubstitutedphenyl.

In some embodiments of Formulas (I) and (II), Cy¹ is cyanophenyl.

In some embodiments of Formulas (I) and (II), Cy¹ is 3-cyanophenyl.

In some embodiments of Formulas (I) and (II), Cy¹ is 3-cyanophenyl or3-cyano-2-fluorophenyl.

In some embodiments of Formulas (I) and (II), Cy¹ is phenyl substitutedby C(O)NR^(c7)R^(d7), wherein R^(c7) and R^(d7) are each independentlyselected from H and C₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), Cy¹ is phenyl substitutedby C(O)NH₂.

In some embodiments of Formulas (I) and (II), Cy¹ is 3-formylphenyl.

In some embodiments of Formulas (I) and (II):

R¹ is H;

Cy¹ is C₆₋₁₀ aryl which is optionally substituted by 1, 2, 3, or 4independently selected R⁷ substituents; and

R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents.

In some embodiments of Formulas (I) and (II):

R¹ is H;

Cy¹ is phenyl which is optionally substituted by 1 or 2 independentlyselected R⁷ substituents; and

R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents.

In some embodiments of the compounds of Formulas (I) and (II):

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4), andS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR¹, NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21);

each R^(c21) and R^(d21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂-6 alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41);

Cy¹ is C₆₋₁₀ aryl which is optionally substituted by 1, 2, 3, or 4independently selected R⁷ substituents;

each R^(a4), R^(b4), R^(c4), and R⁴ is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-6 memberedheterocycloalkyl group;

each R^(a41), R^(b41), R^(c41), and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of the compounds of Formulas (I) and (II):

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), S(O)R^(b2), and S(O)₂R^(b2);

R⁴ is selected from C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR⁴R^(d4), S(O)R^(b4)and S(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41);

Cy¹ is C₆₋₁₀ aryl which is optionally substituted by 1, 2, 3, or 4independently selected R⁷ substituents;

each R^(a4), R^(b4), R^(c4), and R⁴ is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-6 memberedheterocycloalkyl group;

each R^(a41), R^(b41), R^(c41), and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of the compounds of Formulas (I) and (II):

R¹ is H;

R² is selected from C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, wherein the C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R² are each optionallysubstituted with 1 or 2 independently selected R^(2A) substituents;

R⁴ is selected from C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, C(O)NR^(c4)R^(d4), and NR^(c4)C(O)OR^(a4),wherein the C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl-, and (5-6 memberedheteroaryl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with 1 or2 independently selected R^(4A) substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21);

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, andOR^(a41);

Cy¹ is phenyl which is optionally substituted by 1 or 2 independentlyselected R⁷ substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-6 memberedheterocycloalkyl group;

each R^(a41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of the compounds of Formulas (I) and (II):

R¹ is H;

R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and CN;

R⁴ is selected from phenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆alkyl-, C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), wherein each C₁₋₆ alkylis optionally substituted by 1 or 2 OH groups; and the phenyl-C₁₋₆alkyl- is optionally substituted with 1 or 2 independently selected halogroups;

Cy¹ is phenyl which is optionally substituted by 1 or 2 independentlyselected R⁷ substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or, any R^(c4) and R^(d4), attached to the same N atom, together withthe N atom to which they are attached, form a 4-6 memberedheterocycloalkyl group; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of the compounds of Formulas (I) and (II):

R¹ is H;

R² is selected from cyclopropyl, pyrazolyl, pyridyl, pyrimidinyl,dihydropyridin-(2H)-yl, and pyridinonyl, each of which is optionallysubstituted with 1 or 2 independently selected R^(2A) substituents;

R⁴ is selected from C(O)NHC₁₋₆alkyl, C(O)-azetidinyl, C(O)-pyrrolidinyl,C(O)-piperidinyl, C(O)N(C₁₋₆ alkyl)₂, NHC(O)OC₂₋₆ alkyl,(azetidinyl)-C₁₋₆ alkyl, (pyridyl)-C₁₋₆ alkyl, (phenyl)-C₁₋₆ alkyl,(fluorophenyl)-C₁₋₆ alkyl, 3,6-dihydro-2H-pyranyl, NH-(phenyl), andpyridiyl, wherein each C₁₋₆ alkyl and azetidinyl group is optionallysubstituted by 1 or 2 OH groups; and each pyridyl is optionallysubstituted by a methylpiperazinyl group;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21);

Cy¹ is cyanophenyl; and

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of the compounds of Formulas (I) and (II):

R¹ is H;

R² is selected from H, difluoroethyl, bromo, and CN;

R⁴ is selected from phenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆alkyl-, C(O)NR⁴R^(d4), NR^(c4)C(O)OR^(a4), wherein each C₁₋₆ alkyl isoptionally substituted by 1 or 2 OH groups; and the phenyl-C₁₋₆ alkyl-is optionally substituted with 1 or 2 independently selected halogroups;

Cy¹ is cyanophenyl; and

each R^(a4), R^(c4), and R^(d4) is independently selected from H andC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), the compound is a compoundof Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein variables R², R³,R⁴, and Cy¹ are defined according to the definitions provided herein forcompounds of Formulas (I) and (II).

In some embodiments of Formula (IIa),

R³ is H or CN;

Cy¹ is phenyl which is substituted by 1 or 2 independently selected R⁷substituents;

each R⁷ is independently selected from halo and CN;

R² is selected from phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl and4-7 membered heterocycloalkyl, wherein the phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, or 3 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a21),SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21), wherein said phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl of R^(2A) areoptionally substituted with 1, 2, or 3 independently selected R^(2B)substitutents;

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each R^(2B) is independently selected from halo, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4), andS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said C₁₋₆ alkyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R^(a4), R^(b4), R^(c4), and R^(d4) are eachoptionally substituted by 1, 2, or 3 independently selected R^(4A)substituents;

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a41),SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41),OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl of R^(4A) are each optionally substituted by 1or 2 independently selected R^(4B) substituents;

each R^(a41), R^(b41), R^(c41), and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl ofR^(a41), R^(b41), R^(c41), and R^(d41) is optionally substituted by 1,2, or 3 independently selected R^(4B) substituents; and

each R^(4B) is independently selected from halo, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments of Formula (IIa),

R³ is H or CN;

Cy¹ is 3-cyanophenyl or 3-cyano-2-fluorophenyl;

R² is selected from C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, wherein the C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R² are each optionallysubstituted with 1 or 2 independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, and C(O)NR²¹R^(d21), wherein said C₁₋₄ alkyl of R^(2A) isoptionally substituted with 1, 2, or 3 independently selected R^(2B)substitutents;

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(2B) is independently selected from halo and OH.

R⁴ is selected from phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-, C(O)R^(b4),C(O)NR^(c4)R^(d4), and NR^(c4)R^(d4), wherein the phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₃ alkyl-, (5-10membered heteroaryl)-C₁₋₃ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₃ alkyl- of R⁴ are each optionally substituted with1 or 2 independently selected R^(4A) substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, phenyl, and 4-7 membered heterocycloalkyl, wherein saidC₁₋₆ alkyl, phenyl, and 4-7 membered heterocycloalkyl of R^(a4), R^(b4),R^(c4), and R^(d4) are optionally substituted with 1, 2, or 3independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, 4-7 memberedheterocycloalkyl, and OH, wherein said 4-7 membered heterocycloalkyl ofR^(4A) is optionally substituted with 1 or 2 independently selectedR^(4B) substituents; and

each R^(4B) is independently selected from halo, OH, and C₁₋₄ alkyl.

In some embodiments of Formula (IIa),

R³ is H or CN;

Cy¹ is phenyl which is substituted by 1 or 2 independently selected R⁷substituents;

each R⁷ is independently selected from halo and CN;

R² is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and CN;

R⁴ is selected from phenyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆alkyl-, and C(O)NR^(c4)R^(d4), wherein the phenyl-C₁₋₆ alkyl- and (5-6membered heteroaryl)-C₁₋₆ alkyl- of R⁴ are each optionally substitutedwith 1 or 2 substituents independently selected from OH and halo; and

each R^(a4), R^(c4), and R^(d4) is independently selected from H andC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (II), the compound is a compoundof Formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein n is an integerfrom 0 to 4, and wherein variables R², R⁴, and R⁷ are defined accordingto the definitions provided herein for compounds of Formulas (I) and(II).

In some embodiments of Formulas (I) and (II), the compound is a compoundof Formula (IIc):

or a pharmaceutically acceptable salt thereof, wherein variables R, R⁴,and R are defined according to the definitions provided herein forcompounds of Formulas (I) and (II).

In some embodiments, the compound of Formula (I) provided herein, or apharmaceutically acceptable salt thereof, is a compound of Formula(III):

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formulas (I) and (III), R¹ is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl of R¹ areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(1A) substituents.

In some embodiments of Formulas (I) and (III), R¹ is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments of Formulas (I) and (III), R¹ is H or C₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III), R¹ is H.

In some embodiments of Formulas (I) and (III), R² is selected from H,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R² areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents.

In some embodiments of Formulas (I) and (III), R² is selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents.

In some embodiments of Formulas (I) and (III), each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21).

In some embodiments of Formulas (I) and (III), R² is selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR^(a1), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(2A) are eachoptionally substituted by 1, 2, or 3 independently selected R^(2B)substitutents;

each R^(a21), R²⁴¹, R^(c21), and R^(d21) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl of R^(a21),R²⁴¹, R^(c21), and R^(d21) is optionally substituted by 1, 2, or 3independently selected R^(2A) substituents; and

each R^(2B) is independently selected from D, halo, OH, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments of Formulas (I) and (III), R² is selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; and

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21).

In some embodiments of Formulas (I) and (III), R² is selected from 5-10membered heteroaryl and 4-7 membered heterocycloalkyl, wherein the 5-10membered heteroaryl and 4-7 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, or 3 independently selected R^(2A)substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, and OH, wherein said C₁₋₆ alkyl of R^(2A) is optionallysubstituted by 1, 2, or 3 independently selected R^(2B) substitutents;and

each R^(2B) is independently selected from D, halo, and OH.

In some embodiments of Formulas (I) and (III), R² is selected from 5-6membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-6 membered heterocycloalkyl of R² are eachoptionally substituted with 1 or 2 independently selected R^(2A)substituents.

In some embodiments of Formulas (I) and (III), each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21),C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21), OC(O)R^(b21)OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)C(O)R^(b21),NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21) and S(O)R^(b21).

In some embodiments of Formulas (I) and (III), each R^(a21), R^(b21),R^(c21), and R^(d21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (III), R² is selected from 5-6membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the 5-6membered heteroaryl and 4-6 membered heterocycloalkyl of R² are eachoptionally substituted with 1 or 2 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21); and

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (III), R² is a 5-6 memberedheteroaryl, optionally substituted with 1, 2, or 3 independentlyselected R^(2A) substituents.

In some embodiments of Formulas (I) and (III), R² is a 5-6 memberedheteroaryl.

In some embodiments of Formulas (I) and (III), R² is a 5-6 memberedheterocycloalkyl.

In some embodiments of Formulas (I) and (III), R² is selected from6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 4-methyloxazol-5-yl,4-ethyloxazol-5-yl, 3-methylpyridin-4-yl,4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl,2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl,1-ethyl-1H-pyrazol-5-yl, 6-hydroxypyridin-3-yl,2,6-dimethylpyridin-4-yl, 3-methyl-1H-pyrazol-4-yl,[1,2,4]triazolo[4,3-a]pyridin-6-yl, oxazol-5-yl,imidazo[1,2-a]pyridine-6-yl, 3-fluoropyridin-4-yl, and1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl.

In some embodiments of Formulas (I) and (III), R² is selected from6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 4-methyloxazol-5-yl,4-ethyloxazol-5-yl, and 3-methylpyridin-4-yl.

In some embodiments of Formulas (I) and (III), R² is pyridinonyl.

In some embodiments of Formulas (I) and (III), R² is6-oxo-1,6-dihydropyridin-3-yl.

In some embodiments of Formulas (I) and (III), R² is pyrimidin-4-yl.

In some embodiments of Formulas (I) and (III), R² is selected from thegroup consisting of 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl,pyrimidin-4-yl, and 2,6-dimethylpyridin-4-yl.

In some embodiments of Formulas (I) and (III), R⁴ is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionallysubstituted with 1 or 2 independently selected R^(4A) substituents.

In some embodiments of Formulas (I) and (III), each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃-10 cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a41), SR^(a41),NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41),OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),S(O)R^(b41), and S(O)₂R^(b41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4B)substituents.

In some embodiments of Formulas (I) and (III), R⁴ is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (III), R⁴ is H.

In some embodiments of Formulas (I) and (III), R² is selected from H, D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (III), R² is H.

In some embodiments of Formulas (I) and (III), R² is6-oxo-1,6-dihydropyridin-3-yl or imidazo[1,2-a]pyridin-6-yl; and R⁴ isH.

In some embodiments of Formulas (I) and (III), R² is H; and R⁴ is—NHC(O)OC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III), R⁴ is selected fromC(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4), andS(O)₂R^(b4).

In some embodiments of Formulas (I) and (III), each R^(a4), R^(b4),R^(c4), and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (III), R⁴ is selected fromC(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), S(O)R^(b4), andS(O)₂R^(b4); and

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of Formulas (I) and (III), R⁴ is selected fromC(O)NR^(c4)R^(d4) and NR^(c4)C(O)OR^(a4).

In some embodiments of Formulas (I) and (III), R⁴ is NR^(c4)C(O)OR^(a4).

In some embodiments of Formulas (I) and (III), each R^(a4), R^(c4), andR^(d4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III), R⁴ is selected fromC(O)NR^(c4)R^(d4) and NR^(c4)C(O)OR^(a4); and

each R^(a4), R^(c4), and R^(d4) is independently selected from H andC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III), R⁴ is —NHC(O)OC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III), R⁴ is —NHC(O)OCH₂CH₃.

In some embodiments of Formulas (I) and (III), R⁴ is selected from C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,OR^(a4), C(O)R^(b4), C(O)NR⁴R^(d4), C(O)OR^(a4), NR^(c4)R^(d4),S(O)₂NR⁴R^(d4), and S(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are eachoptionally substituted with 1, 2, or 3 independently selected R^(4A)substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(b4), R^(c4) and R^(d4) areeach optionally substituted with 1, 2, or 3 independently selectedR^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, OR^(a41), C(O)R^(b41),C(O)NR⁴¹R^(d41), C(O)OR^(a41), NR^(c41)R^(d41), S(O)₂NR⁴¹R^(d41), andS(O)₂R^(b41), wherein the C₁₋₆ alkyl, 5 C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(4A) are each optionally substituted with 1, 2, or 3independently selected R^(4B) substituents;

each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6membered heteroaryl of R^(a41), R^(b41), R^(c41) and R^(d41) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆ cycloalkyl)-C₁₋₃ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), NR^(c42)R^(d42), S(O)₂NR^(c42)R^(d42), and S(O)₂R^(b42),wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆cycloalkyl)-C₁₋₃ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-,(5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionallysubstituted with 1, 2, or 3 independently selected R^(4C) substituents;

each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6membered heteroaryl of R^(a42), R^(b42), R^(c42) and R^(d42) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4C)substituents;

each R^(4C) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)OR^(a43),NR^(c43)R^(d43), S(O)₂NR^(c43)R^(d43), and S(O)₂R^(b43), wherein theC₁₋₆ alkyl of R^(4C) is optionally substituted with 1 or 2 independentlyselected R^(4D) substituents;

each R^(a43), R^(b43), R^(c43) and R^(d43) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl ofR^(a43), R^(b43), R^(c43) and R^(d43) are each optionally substitutedwith 1 or 2 independently selected R^(4D) substituents;

or, any R^(c43) and R^(d43), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group, wherein the 4-, 5-, or 6-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents; and

each R^(4D) is independently selected from C₁₋₃ alkyl and OH.

In some embodiments of Formulas (I) and (III), R⁴ is selected fromphenyl-C₁₋₃ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-, (5-10membered heteroaryl)-C₁₋₃ alkyl-, OR^(a4), C(O)R^(b4), and S(O)₂R^(b4),wherein the phenyl-C₁₋₃ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃alkyl- and (5-10 membered heteroaryl)-C₁₋₃ alkyl- of R⁴ are eachoptionally substituted with 1, 2, or 3 independently selected R^(4A)substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromphenyl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, wherein the phenyl, 4-7 memberedheterocycloalkyl, and (5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(a4),R^(b4), R^(c4) and R^(d4) are each optionally substituted with 1, 2, or3 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, (4-10 memberedheterocycloalkyl)-C₁₋₃ alkyl-, OR^(a41), S(O)₂R^(b41) andNR^(c41)R^(d41), wherein the C₁₋₆ alkyl, 5-6 membered heteroaryl, and(4-10 membered heterocycloalkyl)-C₁₋₃ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 5-6 membered heteroaryl, whereinthe C₁₋₆ alkyl and 5-6 membered heteroaryl of R^(a41), R^(b41), R^(c41)and R^(d41) are each optionally substituted with 1, 2, or 3independently selected R^(4B) substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)OR^(a42), andNR^(c42)R^(d42), wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionally substituted with1, 2, or 3 independently selected R^(4C) substituents;

each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 5-7membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 5-7 membered heterocycloalkyl of R^(a42),R^(b42), R^(c42) and R^(d42) are each optionally substituted with 1, 2,or 3 independently selected R^(4C) substituents;

each R^(4C) is independently selected from C₁₋₆ alkyl, CN,C(O)NR^(c43)R^(d43), C(O)OR^(a43), NR^(c43)R^(d43), and S(O)₂R^(b43),wherein the C₁₋₆ alkyl of R^(4C) is optionally substituted with 1 or 2independently selected R^(4D) substituents;

each R^(a43), R^(b43), R^(c43) and R^(d43) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl ofR^(a43), R^(b43), R^(c43) and R^(d43) are each optionally substitutedwith 1 or 2 independently selected R^(4D) substituents;

or, any R^(c43) and R^(d43), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group, wherein the 4-, 5-, or 6-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents;

each R^(4D) is independently selected from C₁₋₃ alkyl and OH.

In some embodiments of Formulas (I) and (III), R⁴ is selected from C₆₋₁₀aryl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, OR^(a4),C(O)R^(b4), and S(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl- and(5-10 membered heteroaryl)-C₁₋₆ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents; and

each R^(4A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, OR^(a41), SR^(a41), and NR⁴¹R^(d41),wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4B)substituents.

In some embodiments of Formulas (I) and (III), R⁴ is selected from C₆₋₁₀aryl-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-, OR^(a4),C(O)R^(b4), and S(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl- and(5-10 membered heteroaryl)-C₁₋₃ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₃ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₃alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₃ alkyl-, CN, OR^(a41), SR^(a41), and NR⁴¹R^(d41),wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₃ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₃ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a42), COOR^(a42), and NR^(c42)R^(d42);

each R^(a4) and R^(b4) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, phenyl, and azetidinyl wherein the phenyl is optionallysubstituted with 1 or 2 groups selected from halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

each R^(a41), R^(c41) and R^(d41) is independently selected from H andC₁₋₆ alkyl; and

each R^(a42), R^(c42) and R^(d42) is independently selected from H andC₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III), R⁴ is selected from C₆₋₁₀aryl-C₁₋₃ alkyl- and (5-10 membered heteroaryl)-C₁₋₃ alkyl- wherein theC₆₋₁₀ aryl-C₁₋₃ alkyl- and (5-10 membered heteroaryl)-C₁₋₃ alkyl- of R⁴are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, and OR^(a41); and

each R^(a41) is independently selected from H and C₁₋₃ alkyl.

In some embodiments of Formulas (I) and (III), R⁴ is C₆ aryl-C₁₋₃alkyl-optionally substituted with 1, 2, or 3 substituents independentlyselected from OH and halo.

In some embodiments of Formulas (I) and (III), R⁴ is selected frompyridin-2-ylmethyl, 1H-Pyrrolo[2,3-b]pyridin-1-yl,7H-pyrrolo[2,3-b]pyridin-7-yl, 2-fluorophenoxy,hydroxy(pyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl,(imidazo[1,2-a]pyridin-8-yl)methyl, (pyrazolo[1,5-a]pyridin-7-yl)methyl,(2H-indazol-2-yl)methyl, (1H-indazol-1-yl)methyl,(2,6-difluorophenyl)(hydroxy)methyl,(2,5-difluorophenyl)(hydroxy)methyl,(2,3-difluorophenyl)(hydroxy)methyl, (2-fluorophenyl)(hydroxy)methyl,(2-chlorophenyl)(hydroxy)methyl, hydroxy(phenyl)methyl, phenylsulfonyl,azetidine-1-carbonyl, benzo[d]oxazol-4-ylmethyl,2-fluoro-6-(1-methyl-1H-pyrazol-5-yl)benzyl,2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl,2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)benzyl,2-fluoro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl,2-fluoro-6-((3-oxopiperazin-1-yl)methyl)benzyl,2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl,2-fluoro-6-(((2-methyl-2H-1,2,3-triazol-4-yl)amino)methyl)benzyl,2-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl,amino(2,6-difluorophenyl)methyl,(2,6-difluorophenyl)(methylamino)methyl,(2,6-difluorophenyl)((2-hydroxyethyl)amino)methyl,amino(2-fluorophenyl)methyl, amino(2,6-difluorophenyl)methyl,(3-(oxazol-5-yl)pyridin-2-yl)methyl,2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)benzyl,(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-yl)methyl,2-((1-acetylpiperidin-4-yl)methyl)-6-fluorobenzyl,(2-(difluoromethoxy)-6-fluorophenyl)(hydroxy)methyl,2-fluoro-6-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)benzyl,(2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl,2-fluoro-6-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)benzyl,(2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl,2-fluoro-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)benzyl,2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)(hydroxy)methyl,2-fluoro-6-(1-((trans)-3-(methylamino)cyclobutyl)-1H-pyrazol-4-yl)benzyl,2-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-6-fluorobenzyl,2-fluoro-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)benzyl,(3-methylpyridin-2-yl)methoxy,(3-((1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl,(3-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl,(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl,2-((3-hydroxypyrrolidin-1-yl)methyl)benzyl, and(6-methoxypyridin-2-yl)methyl.

In some embodiments of Formulas (I) and (III), R⁴ is selected frompyridin-2-ylmethyl, 1H-pyrrolo[2,3-b]pyridin-1-yl,7H-pyrrolo[2,3-b]pyridin-7-yl, 2-fluorophenoxy,hydroxy(pyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl,imidazo[1,2-a]pyridin-8-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl,(2H-Indazol-2-yl)methyl, 1H-indazol-1-yl)methyl,(2,6-difluorophenyl)(hydroxy)methyl,(2,5-difluorophenyl)(hydroxy)methyl,(2,3-difluorophenyl)(hydroxy)methyl, (2-fluorophenyl)(hydroxy)methyl,(2-chlorophenyl)(hydroxy)methyl, hydroxy(phenyl)methyl, phenylsulfonyl,and azetidine-1-carbonyl.

In some embodiments of Formulas (I) and (III), Cy¹ is C₆₋₁₀ aryl whichis optionally substituted by 1, 2, 3, or 4 independently selected R⁷substituents.

In some embodiments of Formulas (I) and (III), Cy¹ is phenyl which isoptionally substituted by 1 or 2 independently selected R⁷ substituents.

In some embodiments of Formulas (I) and (III), each R⁷ is independentlyselected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (III), Cy¹ is phenyl which isoptionally substituted by 1 or 2 independently selected R⁷ substituents;and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (III), Cy¹ is phenyl which issubstituted by 1 or 2 independently selected R⁷ substituents; and

each R⁷ is independently selected from halo and CN.

In some embodiments of Formulas (I) and (III), Cy¹ is phenyl which isoptionally substituted by 1 or 2 substituents independently selectedfrom C₁₋₆ alkyl, halo, and CN.

In some embodiments of Formulas (I) and (III), Cy¹ is phenyl which isoptionally substituted by 1 or 2 substituents independently selectedfrom C₁₋₆ alkyl and CN.

In some embodiments of Formulas (I) and (III), Cy¹ is unsubstitutedphenyl.

In some embodiments of Formulas (I) and (III), Cy¹ is cyanophenyl orcyanofluorophenyl.

In some embodiments of Formulas (I) and (III), Cy¹ is cyanophenyl.

In some embodiments of Formulas (I) and (III), Cy¹ is 3-cyanophenyl or3-cyano-2-fluorophenyl.

In some embodiments of Formulas (I) and (III):

R¹ is H;

Cy¹ is C₆₋₁₀ aryl which is optionally substituted by 1, 2, 3, or 4independently selected R⁷ substituents; and

R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents.

In some embodiments of Formulas (I) and (III):

R¹ is H;

Cy¹ is phenyl which is optionally substituted by 1 or 2 independentlyselected R⁷ substituents; and

R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents.

In some embodiments of Formulas (I) and (III):

R¹ is H or C₁₋₆ alkyl;

R² is 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3independently selected R^(2A) substituents;

R⁴ is selected from C₆₋₁₀ aryl-C₁₋₃ alkyl-, (5-10 memberedheteroaryl)-C₁₋₃ alkyl-, OR^(a4), C(O)R^(b4), and S(O)₂R^(b4), whereinthe C₆₋₁₀ aryl-C₁₋₃ alkyl- and (5-10 membered heteroaryl)-C₁₋₃ alkyl- ofR⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₃ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₃alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₃ alkyl-, CN, OR^(a41), SR^(a41), and NR⁴¹R^(d41),wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₃ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₃ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a42), COOR^(a42), and NR^(c42)R^(d42).

Cy¹ is phenyl which is optionally substituted by 1, 2, or 3independently selected R⁷ substituents;

each R^(a4) and R^(b4) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, phenyl, and azetidinyl wherein the phenyl is optionallysubstituted with 1 or 2 groups selected from halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

each R^(a41), R^(c41), and R^(d41) is independently selected from H andC₁₋₆ alkyl;

each R^(a42), R^(c42), and R^(d42) is independently selected from H andC₁₋₆ alkyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,and CN.

In some embodiments of Formulas (I) and (III):

R¹ is H or C₁₋₆ alkyl;

R² is 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3independently selected R^(2A) substituents;

R⁴ is selected from C₆₋₁₀ aryl-C₁₋₃ alkyl- and (5-10 memberedheteroaryl)-C₁₋₃ alkyl-, wherein the C₆₋₁₀ aryl-C₁₋₃ alkyl- and (5-10membered heteroaryl)-C₁₋₃ alkyl- of R⁴ are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, and OR^(a41);

Cy¹ is phenyl which is optionally substituted by 1 or 2 substituentsindependently selected from C₁₋₆ alkyl and CN; and

each R^(a41) is independently selected from H and C₁₋₃ alkyl.

In some embodiments of Formulas (I) and (III):

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl;

R⁴ is selected from C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4) S(O)R^(b4), andS(O)₂R^(b4);

Cy¹ is C₆₋₁₀ aryl which is optionally substituted by 1, 2, 3, or 4independently selected R⁷ substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (III):

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21);

Cy¹ is C₆₋₁₀ aryl which is optionally substituted by 1, 2, 3, or 4independently selected R⁷ substituents;

each R^(a21), R^(b2), R^(c21), and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl;

R⁴ is selected from C(O)NR⁴R^(d4) and NR^(c4)C(O)OR^(a4);

Cy¹ is phenyl which is optionally substituted by 1 or 2 independentlyselected R⁷ substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H andC₁₋₆ alkyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is selected from 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl of R² are each optionally substituted with 1 or 2independently selected R^(2A) substituents;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a21), SR^(a21),NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),and S(O)R^(b21);

Cy¹ is phenyl which is optionally substituted by 1 or 2 independentlyselected R⁷ substituents;

each R^(a21), R^(b21), R^(c21), and R^(d21) is independently selectedfrom H and C₁₋₆ alkyl; and

each R⁷ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, and NO₂.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is H;

R⁴ is NR^(c4)C(O)OR^(a4);

Cy¹ is cyanophenyl; and

R^(a4) and R^(c4) are each independently selected from H and C₁₋₆ alkyl.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is selected from 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

R⁴ is H; and

Cy¹ is cyanophenyl.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is selected from 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 or 2 C₁₋₃ alkylgroups;

R⁴ is phenyl-C₁₋₃ alkyl- or pyridyl-C₁₋₃ alkyl-, wherein the phenyl-C₁-3alkyl- and pyridyl-C₁₋₃ alkyl- are each optionally substituted with 1,2, or 3 substituents independently selected from OH and halo; and

Cy¹ is cyanophenyl.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is selected from 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl;

R⁴ is phenyl-C₁₋₃ alkyl- optionally substituted with 1, 2, or 3substituents independently selected from OH and halo; and

Cy¹ is cyanophenyl.

In some embodiments of Formulas (I) and (III):

R¹ is H;

R² is pyrimidin-4-yl;

R⁴ is phenyl-C₁₋₃ alkyl- optionally substituted with 1, 2, or 3substituents independently selected from OH and halo; and

Cy¹ is cyanophenyl.

In some embodiments of Formulas (I) and (III), the compound is acompound of Formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein variables R², R⁴,and Cy¹ are defined according to the definitions provided herein forcompounds of Formulas (I) and (III).

In some embodiments of Formula (IIIa),

Cy¹ is phenyl which is substituted by 1 or 2 independently selected R⁷substituents;

each R⁷ is independently selected from halo and CN;

R² is selected from H, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, or4 independently selected R^(2A) substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R²¹,S(O)R^(b21), and S(O)₂R^(b21), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(2A) are eachoptionally substituted by 1, 2, or 3 independently selected R^(2B)substitutents;

each R^(a21), R²⁴¹, R^(c21), and R^(d21) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl of R^(a21),R²⁴¹, R^(c21), and R^(d21) is optionally substituted by 1, 2, or 3independently selected R^(2A) substituents; and

each R^(2B) is independently selected from D, halo, OH, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

R⁴ is selected from C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), S(O)₂NR^(c4)R^(d4), and S(O)₂R^(b4), whereinthe C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1, 2, or 3independently selected R^(4A) substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(b4), R^(c4) and R^(d4) areeach optionally substituted with 1, 2, or 3 independently selectedR^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, OR^(a41), C(O)R^(b41),C(O)NR⁴¹R^(d41), C(O)OR^(a41), NR^(c41)R^(d41), S(O)₂NR⁴¹R^(d41), andS(O)₂R^(b41), wherein the C₁₋₆ alkyl, 5 C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(4A) are each optionally substituted with 1, 2, or 3independently selected R^(4B) substituents;

each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6membered heteroaryl of R^(a41), R^(b41), R^(c41) and R^(d41) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆ cycloalkyl)-C₁₋₃ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), NR^(c42)R^(d42), S(O)₂NR⁴²R^(d42), and S(O)₂R^(b42),wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆cycloalkyl)-C₁₋₃ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-,(5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionallysubstituted with 1, 2, or 3 independently selected R^(4C) substituents;

each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6membered heteroaryl of R^(a42), R^(b42), R^(c42) and R^(d42) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4C)substituents;

each R^(4C) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)OR^(a43),NR^(c43)R^(d43), S(O)₂NR^(c43)R^(d43), and S(O)₂R^(b43), wherein theC₁₋₆ alkyl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4C) are each optionally substituted with 1or 2 independently selected R^(4D) substituents;

each R^(a43), R^(b43), R^(c43) and R^(d43) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl ofR^(a43), R^(b43), R^(c43) and R^(d43) are each optionally substitutedwith 1 or 2 independently selected R^(4D) substituents;

or, any R^(c43) and R^(d43), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group, wherein the 4-, 5-, or 6-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents; and

each R^(4D) is independently selected from C₁₋₃ alkyl and OH.

In some embodiments of Formula (IIIa),

Cy¹ is 3-cyanophenyl or 3-cyano-2-fluorophenyl;

R² is selected from H, 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl, wherein the 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, or 3independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, and OH, wherein said C₁₋₆ alkyl of R^(2A) is optionallysubstituted by 1, 2, or 3 independently selected R^(2B) substitutents;

each R^(2B) is independently selected from D, halo, and OH;

R⁴ is selected from phenyl-C₁₋₃ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-,OR^(a4), C(O)R^(b4), and S(O)₂R^(b4), wherein the phenyl-C₁₋₃ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₃ alkyl- and (5-10 memberedheteroaryl)-C₁₋₃ alkyl- of R⁴ are each optionally substituted with 1, 2,or 3 independently selected R^(4A) substituents;

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromphenyl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, wherein the phenyl, 4-7 memberedheterocycloalkyl, and (5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(a4),R^(b4), R^(c4) and R^(d4) are each optionally substituted with 1, 2, or3 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, (4-10 memberedheterocycloalkyl)-C₁₋₃ alkyl-, OR^(a41), S(O)₂R^(b41) and NR⁴¹R^(d41),wherein the C₁₋₆ alkyl, 5-6 membered heteroaryl, and (4-10 memberedheterocycloalkyl)-C₁₋₃ alkyl- of R^(4A) are each optionally substitutedwith 1, 2, or 3 independently selected R^(4B) substituents;

each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 5-6 membered heteroaryl, whereinthe C₁₋₆ alkyl and 5-6 membered heteroaryl of R^(a41), R^(b41), R^(c41)and R^(d41) are each optionally substituted with 1, 2, or 3independently selected R^(4B) substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)OR^(a42), andNR^(c42)R^(d42), wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionally substituted with1, 2, or 3 independently selected R^(4C) substituents;

each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 5-7membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 5-7 membered heterocycloalkyl of R^(a42),R^(b42), R^(c42) and R^(d42) are each optionally substituted with 1, 2,or 3 independently selected R⁴c substituents;

each R^(4C) is independently selected from C₁₋₆ alkyl, CN,C(O)NR^(c43)R^(d43), C(O)OR^(a43), NR^(c43)R^(d43), and S(O)₂R^(b43),wherein the C₁₋₆ alkyl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4C) are each optionally substituted with 1or 2 independently selected R^(4D) substituents;

each R^(a43), R^(b43), R^(c43) and R^(d43) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl ofR^(a43), R^(b43), R^(c43) and R^(d43) are each optionally substitutedwith 1 or 2 independently selected R^(4D) substituents;

or, any R^(c43) and R^(d43), attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group, wherein the 4-, 5-, or 6-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents; and

each R^(4D) is independently selected from C₁₋₃ alkyl and OH.

In some embodiments of Formula (IIIa),

R² is selected from 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl, wherein the 5-6 membered heteroaryl and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 or 2 C₁₋₃ alkylgroups;

R⁴ is phenyl-C₁₋₃ alkyl- or pyridyl-C₁₋₃ alkyl-, wherein the phenyl-C₁₋₃alkyl- and pyridyl-C₁₋₃ alkyl- are each optionally substituted with 1,2, or 3 substituents independently selected from OH and halo; and

Cy¹ is 3-cyanophenyl.

In some embodiments of Formulas (I) and (III), the compound is acompound of Formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein n is an integerfrom 0 to 4, and wherein variables R², R⁴, and R⁷ are defined accordingto the definitions provided herein for compounds of Formulas (I) and(III).

In some embodiments of Formulas (I) and (III), the compound is acompound of Formula (IIIc):

or a pharmaceutically acceptable salt thereof, wherein variables R², R⁴,and R⁷ are defined according to the definitions provided herein forcompounds of Formulas (I) and (III).

In some embodiments, the compound is the (S)-enantiomer of one of thepreceding compounds, or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound is the (R)-enantiomer of one of thepreceding compounds, or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurence‘variable’ is selected from.”

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 5 to 10 carbon atoms. In some embodiments, the arylgroup is phenyl or naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In someembodiments, a halo is F. In some embodiments, a halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “cyano-C_(1-n) alkyl” refers to a group offormula —(C_(1-n) alkylene)-CN, wherein the alkyl group has 1 to ncarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms, e.g., —(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C_(1-n) alkyl” refers to a group of formula—(C_(1-n) alkylene)-OH, wherein the alkyl group has 1 to n carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms, e.g., —(C₁₋₃ alkylene)-OH.

As used herein, the term “C_(1-n) alkoxy-C_(1-n) alkyl” refers to agroup of formula —(C_(1-n) alkylene)-O(C_(1-n) alkyl), wherein the alkylgroup has 1 to n carbon atoms. In some embodiments, the alkyl group has1 to 6, 1 to 4, or 1 to 3 carbon atoms, e.g., —(C₁₋₆ alkylene)-O(C₁₋₆alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” is a group offormula —OC(O)— alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m) alkylaminocarbonyloxy” is a group of formula—OC(O)—NH— alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “di(C_(n-m) alkyl)aminocarbonyloxy” is a group offormula —OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, nto m carbon atoms.

As used herein “C_(n-m) alkoxycarbonylamino” refers to a group offormula —NHC(O)O(C_(n-m) alkyl), wherein the alkyl group has n to mcarbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,or 10 ring-forming carbons (i.e., C₃-10). In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl.

In some embodiments, the cycloalkyl is a C₄₋₇ monocyclic cycloalkyl. Insome embodiments, the cycloalkyl is a C₄₋₁₀ spirocycle or bridgedcycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, S, and B. In some embodiments, the heteroaryl is a5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2heteroatom ring members independently selected from N, O, S, and B. Insome embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1or 2 heteroatom ring members independently selected from N, O, and S. Insome embodiments, the heteroaryl group contains 3 to 10, 4 to 10, 5 to10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments,the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1ring-forming heteroatom. When the heteroaryl group contains more thanone heteroatom ring member, the heteroatoms may be the same ordifferent. Example heteroaryl groups include, but are not limited to,thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl,benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl,triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl,1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, and thelike.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of a heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). When a ring-forming carbon atom or heteroatom of aheterocycloalkyl group is optionally substituted by one or more oxo orsulfide, the O or S of said group is in addition to the number ofring-forming atoms specified herein (e.g., a1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-memberedheterocycloalkyl group, wherein a ring-forming carbon atom issubstituted with an oxo group, and wherein the 6-memberedheterocycloalkyl group is further substituted with a methyl group).Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having2 fused rings) systems. Included in heterocycloalkyl are monocyclic andpolycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 memberedheterocycloalkyl groups. Heterocycloalkyl groups can also includespirocycles and bridged rings (e.g., a 5 to 10 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S, andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments,the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1to 2 heteroatoms or 1 heteroatom. In some embodiments, theheterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1or 2 heteroatoms independently selected from N, O, S and B and havingone or more oxidized ring members. In some embodiments, theheterocycloalkyl is a monocyclic or bicyclic 5-10 memberedheterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selectedfrom N, O, S, and B and having one or more oxidized ring members. Insome embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from N, O, and S and having one or more oxidizedring members. In some embodiments, the heterocycloalkyl is a monocyclic5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from N, O, and S and having one or more oxidizedring members.

Example heterocycloalkyl groups include pyrrolidin-2-one (or2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran,oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline,benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxo-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxo-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl,oxo-2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[1,2-a]pyrazinyl,3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl and the like. Forexample, heterocycloalkyl groups include the following groups (with andwithout N-methyl substitution):

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, an “alkyl linking group” is a bivalent straight chain orbranched alkyl linking group (“alkylene group”). For example, “C_(o-p)cycloalkyl-C_(n-m) alkyl-”, “C_(o-p) aryl-C_(n-m) alkyl-”,“phenyl-C_(n-m) alkyl-”, “heteroaryl-C_(n-m) alkyl-”, and“heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linking groups. Examplesof “alkyl linking groups” or “alkylene groups” include methylene,ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl,propan-1,1-diyl and the like.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl, or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent, e.g., R⁷ or R^(2A), areindependently selected at each occurrence from the applicable list.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present disclosure can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

As will be appreciated by thosed skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

Compounds of formula 1-14 and 1-15 can be prepared via the syntheticroute outlined in Scheme 1. Alkylation of commercially availablestarting material 1-1 with carbonyl adduct 1-2 (Hal is a halide, such asF, Cl, Br, or I), followed by a condensation reaction at elevatedtemperature, using an appropriate reagent, such as ammonium acetate,generates bicyclic compound 1-3. Compound 1-3 can then react withreagents, such as phosphoryl chloride (POCl₃), to give intermediate 1-4.A nucleophilic aromatic substitution (S_(N)Ar) reaction of intermediate1-4 with amine adduct 1-5 (PG is a suitable protecting group, such as2,4-dimethoxybenzyl), followed by reduction of the ester functionalitywith a suitable reductant (e.g., DIBAL-H), affords alcohol 1-6.Halogenation of 1-6 with an appropriate reagent, such as phosphoroustribromide (PBr₃), generates intermediate 1-7. Compound 1-7 can then becross-coupled with an adduct of formula 1-8, in which M is a boronicacid, boronic ester or an appropriately substituted metal [e.g., M isB(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard Suzuki cross-couplingconditions (e.g., in the presence of a palladium catalyst and a suitablebase), or standard Stille cross-coupling conditions (e.g., in thepresence of a palladium catalyst), or standard Negishi cross-couplingconditions (e.g., in the presence of a palladium catalyst) to afford thecross-coupling product, which undergoes protecting group removal togenerate intermediate 1-9. In some embodiments, Cy⁴ can be a R⁴ or aR⁴-R⁴a. Halogenation of 1-9 with an appropriate reagent, such asN-bromosuccinimide (NBS), affords two isomers 1-10 and 1-11. The finalproducts 1-14 and 1-15 can then be prepared by reacting the two isomers1-10 and 1-11 with either adduct 1-12 or 1-13 using reaction conditionssimilar to that described for the preparation of 1-9 from 1-7.

Compounds of formula 2-7 can be prepared via the synthetic routeoutlined in Scheme 2. Alkylation of commercially available startingmaterial 2-1 (Hal is a halide, such as F, Cl, Br, or I) with carbonyladduct 1-2, followed by condensation using an appropriate reagent, suchas ammonium acetate, at elevated temperature generates bicyclic compound2-2. Compound 2-2 can then react with a suitable reagent, such asphosphoryl chloride (POCl₃), to give intermediate 2-3. A nucleophilicaromatic substitution (S_(N)Ar) reaction of intermediate 2-3 with amineadduct 1-5 (PG is a suitable protecting group, such as2,4-dimethoxybenzyl), followed by removal of the protecting group,affords compound 2-4. Halogenation of 2-4 with a suitable reagent, suchas N-bromosuccinimide (NBS), gives compound 2-5. Intermediate 2-5 can becross-coupled with an adduct of formula 1-12, in which M is a boronicacid, boronic ester or an appropriately substituted metal [e.g., M isB(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard Suzuki cross-couplingconditions (e.g., in the presence of a palladium catalyst and a suitablebase), or standard Stille cross-coupling conditions (e.g., in thepresence of a palladium catalyst), or standard Negishi cross-couplingconditions (e.g., in the presence of a palladium catalyst) to affordcompound 2-6. Intermediate 2-6 then undergoes a second cross-couplingreaction with compound 1-8, using a similar procedure as described forthe preparation of 2-6 from 2-5, to generate the product 2-7.

Compounds of formula 3-6 can be prepared via the synthetic routeoutlined in Scheme 3. A nucleophilic aromatic substitution (S_(N)Ar)reaction of compound 1-4 (prepared using procedures described inScheme 1) with amine adduct 1-5 (PG is a suitable protecting group, suchas 2,4-dimethoxybenzyl), followed by removal of the protecting group,affords intermediate 3-1. Halogenation of 3-1 with an appropriatereagent, such as N-bromosuccinimide (NBS), followed by reduction of theester functionality with a suitable reductant (e.g., DIBAL-H), generatesalcohol 3-2. Intermediate 3-2 can then be oxidized with an appropriateoxidant (e.g., Dess-Martin periodinane) to afford aldehyde 3-3. Anaddition reaction between 3-3 and 3-4 (M¹ is a metal group, such as MgBror Li) then affords secondary alcohol 3-5. The final product 3-6 can beprepared via a cross-coupling reaction between intermediate 3-5 and anadduct of formula 1-12, in which M is a boronic acid, boronic ester oran appropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst).

Compound of formula 4-5 can be prepared via the synthetic route outlinedin Scheme 4. A halogenation reaction of compound 3-1 (prepared usingprocedures from Scheme 3) with an appropriate reagent, such asN-bromosuccinimide (NBS), affords compound 4-1 (Hal is a halide, such asF, Cl, Br, or I). Compound 4-1 can then be cross-coupled with an adductof formula 1-12, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst) to generate intermediate 4-2.Hydrolysis of 4-2 with a suitable reagent, such as sodium hydroxide,gives carboxylic acid 4-3. Compound 4-3 can then react with amine 4-4under standard amide coupling conditions, such as using HATU as couplingreagent and DIPEA as base, to generate product 4-5.

Compounds of formula 5-7 can be prepared via the synthetic routeoutlined in Scheme 5. A nucleophilic aromatic substitution (S_(N)Ar)reaction of commercially available starting material 5-1 (Hal is ahalide, such as F, Cl, Br, or I) with amine 1-5 (PG is a suitableprotecting group, such as 2,4-dimethoxybenzyl) affords compound 5-2.Compound 5-2 can then be cross-coupled with an adduct of formula 5-3, inwhich M is a boronic acid, boronic ester or an appropriately substitutedmetal [e.g., M is B(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard Suzukicross-coupling conditions (e.g., in the presence of a palladium catalystand a suitable base), or standard Stille cross-coupling conditions(e.g., in the presence of a palladium catalyst), or standard Negishicross-coupling conditions (e.g., in the presence of a palladiumcatalyst) to generate intermediate 5-4. The protecting group in 5-4 canbe removed to give compound 5-5. Halogenation of 5-5 with an appropriatereagent, such as N-bromosuccinimide (NBS), affords intermediate 5-6.Compound 5-6 can then be cross-coupled with an adduct of formula 1-12 togive the product 5-7, using a procedure similar to that described forthe preparation of 5-4 from 5-2.

Compounds of formula 6-9 can be prepared via the synthetic routeoutlined in Scheme 6. Commercially available starting material 6-1 (Halis a halide, such as F, Cl, Br, or I) can react with an appropriatereagent, such as t-butyl O-mesitylene carbamate (Journal of HeterocyclicChemistry, 1975, 12, 107), to form pyrazinium salt 6-2. Intermediate 6-2can then undergo a condensation reaction with an adduct of formula 6-3to form compound 6-4. A nucleophilic aromatic substitution (S_(N)Ar)reaction of 6-4 with amine 1-5 (PG is a suitable protecting group, suchas 2,4-dimethoxybenzyl) affords compound 6-5. Compound 6-6 can then beprepared via a cross-coupling reaction between intermediate 6-5 and anadduct of formula 5-3, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst). The protecting group in 6-6 can beremoved to afford compound 6-7, which undergoes a halogenation reactionusing an appropriate reagent, such as N-bromosuccinimide (NBS), to formcompound 6-8. The final product 6-9 can be synthesized by coupling 6-8with an adduct of formula 1-12, using similar procedures as describedfor the preparation of compound 6-6 from 6-5.

Compounds of formula 7-9 can be prepared via the synthetic routeoutlined in Scheme 7. Alkylation of commercially available startingmaterial 7-1 (Hal is a halide, such as F, Cl, Br, or I) with carbonyladduct 1-2, followed by a condensation reaction at elevated temperature,using an appropriate reagent, such as ammonium acetate, generatesbicyclic compound 7-2. Compound 7-2 can then react with reagents, suchas phosphoryl chloride (POCl₃), to give intermediate 7-3. A nucleophilicaromatic substitution (S_(N)Ar) reaction of intermediate 7-3 with amineadduct 7-4 (PG is a suitable protecting group, such as 4-methoxybenzyl)affords intermediate 7-5. Compound 7-5 can then be cross-coupled with anadduct of formula 7-6, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki Cross-Coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst) to generate compound 7-7. Theprotecting groups in 7-7 are removed, and the resulting intermediateundergoes a halogenation reaction with an appropriate reagent, such asN-Bromosuccinimide (NBS), to afford adduct 7-8. The final product 7-9can then be synthesized by coupling 7-8 with an adduct of formula 1-12,using similar procedures as described for the preparation of compound7-7 from 7-5.

Compounds of formula 8-7, 8-10, and 8-11 can be prepared via thesynthetic route outlined in Scheme 8. Compound 7-5 (can be prepared asdescribed in Scheme 7) can first be cross-coupled with reagent offormula 8-1, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki Cross-Coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst) to generate compound 8-2. Ahalogenation reaction of 8-2 can then be carried out using anappropriate reagent, such as 1-bromopyrrolidine-2,5-dione, to affordintermediate 8-3. Another cross-coupling reaction between 8-3 andreagent 1-12 can then be performed using similar conditions as describedfor the transformation from 7-5 to 8-2 to deliver compound 8-4. Thevinyl group in 8-4 is cleaved under suitable conditions, such as usingosmium (VIII) oxide and sodium periodate, and the resulting aldehyde 8-5is reacted with 3-4 in an 1,2-addition reaction (M¹ is a metal group,such as MgCl or Li) to generate alcohol 8-6. The protecting group (PG)in 8-6 can then be removed to generate the desired product 8-7.

On the other hand, aldehyde 8-5 can undergo a reduction reaction usingappropriate reagents, such as NaBH₄, to afford alcohol 8-8. Ahalogenation reaction of 8-8 then affords intermediate 8-9 usingreagents such as PBr₃. A cross-coupling reaction between 8-9 and 1-8(using conditions described for the synthesis of 8-2 from 7-5), followedby the removal of protecting groups (PG), will generate product 8-10.Alternatively, 8-9 can react with amine 4-4 in a nucleophilicsubstitution (S_(N)2) reaction, followed by removal of protecting groups(PG), to afford product 8-11. The reaction sequence described in thisscheme can be rearranged and adjusted accordingly to fit the need ofeach analogue synthesis.

Compounds of formula 9-9 can be prepared using the synthetic routeoutlined in Scheme 9. Commercially available starting material 9-1 (Halis a halide, such as F, Cl, Br, or I) can be subjected to nucleophilicaromatic substitution (S_(N)Ar) with amine 7-4 (PG is a suitableprotecting group, such as 4-methoxybenzyl) to afford compound 9-2.Intermediate 9-2 can react with an appropriate reagent, such asO-(mesitylsulfonyl)hydroxylamine (Journal of Heterocyclic Chemistry,1975, 12, 107), to form pyrazinium salt 9-3. Intermediate 9-3 can thenundergo a condensation reaction with an intermediate of formula 9-4 toform compound 9-5. Compound 9-6 can then be prepared using across-coupling reaction between intermediate 9-5 and an intermediate offormula 5-3, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst). Compound 9-6 can undergo halogenationusing an appropriate reagent, such as N-bromosuccinimide (NBS), to formcompound 9-7. Compound 9-8 can be synthesized by coupling 9-7 with anintermediate of formula 1-12, using similar procedures as described forthe preparation of compound 9-6 from 9-5. The final product 9-9 can beformed after removal of the protecting group in intermediate 9-8.Certain synthetic steps described herein can be rearranged, and/oromitted, to prepare different analogues.

Methods of Use

The compounds of the present disclosure can modulate the activity ofadenosine receptors, such as subtypes A2A and A2B receptors.Accordingly, the compounds, salts or stereoisomers described herein canbe used in methods of inhibiting adenosine receptors (e.g., A2A and/orA2B receptors) by contacting the receptor with any one or more of thecompounds, salts, or compositions described herein. In some embodiments,the compounds or salts can be used in methods of inhibiting activity ofan adenosine receptor in an individual/patient in need of the inhibitionby administering an effective amount of a compound or salt of describedherein. In some embodiments, modulating is inhibiting. In someembodiments, the contacting is in vivo. In some embodiments, thecontacting is ex vivo or in vitro.

The compounds or salts described herein can be selective. By“selective,” it is meant that the compound binds to or inhibits anadenosine receptor with greater affinity or potency, respectively,compared to at least one other receptor, kinase, etc. The compounds ofthe present disclosure can also be dual antagonists (i.e., inhibitors)of adenosine receptors, e.g., A2A and A2B adenosine receptors.

Another aspect of the present disclosure pertains to methods of treatingan adenosine receptor associated disease or disorder in an individual(e.g., patient) by administering to the individual in need of suchtreatment a therapeutically effective amount or dose of one or morecompounds of the present disclosure or a pharmaceutical compositionthereof. An adenosine receptor associated disease or disorder caninclude any disease, disorder or condition that is directly orindirectly linked to expression or activity of the adenosine receptor,including overexpression and/or abnormal activity levels.

The compounds of the present disclosure are useful in the treatment ofdiseases related to the activity of adenosine receptors including, forexample, cancer, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, immunomodulatory disorders, central nervesystem diseases, and diabetes.

Based on the compelling roles of adenosine, e.g., A2A, A2B, receptors inmultiple immunosuppressive mechanisms, developing inhibitors can boostthe immune system to suppress tumor progression. Adenosine receptorinhibitors can be used to treat, alone or in combination with othertherapies, bladder cancer, lung cancer (e.g., non-small cell lung cancer(NSCLC), lung metastasis), melanoma (e.g., metastatic melanoma), breastcancer, cervical cancer, ovarian cancer, colorectal cancer, pancreaticcancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer,thyroid cancer, liver cancer, uterine cancer, head and neck cancer, andrenal cell carcinoma (Antonioli, L. et al., Nature Reviews Cancer, 2013,13, 842-857). See also,https://globenewswire.com/news-release/2017/04/04/954192/0/en/Corvus-Pharmaceuticals-Announces-Interim-Results-from-Ongoing-Phase-1-b-Study-Demonstrating-Safety-and-Clinical-Activity-of-Lead-Checkpoint-Inhibitor-CPI-444-in-Patients-with-Adva.html;Cekic C. et al., J Immunol, 2012, 188:198-205; Iannone, R. et al., Am.J. Cancer Res. 2014, 4:172-181 (study shows that both A2A and CD73blockade enhance the antitumor activity of anti-CTLA-4 mAb therapy in aB16F10 murine melanoma model); Iannone, R. et al., Neoplasia, 2013,15:1400-1410 and Beavis P A., et al., Proc Natl Acad Sci. USA, 2013,110:14711-14716 (study shows that A2A and CD73 blockade decreasedmetastasis in 4T1 breast tumor model with has high CD73 expression). Insome embodiments, the prostate cancer is metastatic castrate-resistantprostate carcinoma (mCRPC). In some embodiments, the colorectal canceris colorectal carcinoma (CRC).

In some embodiments, the disease or disorder is lung cancer (e.g.,non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer,head and neck squamous cell carcinoma, prostate cancer, liver cancer,color cancer, endometrial cancer, bladder cancer, skin cancer, cancer ofthe uterus, renal cancer, gastric cancer, or sarcoma. In someembodiments, the sarcoma is Askin's tumor, sarcoma botryoides,chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma,malignant schwannoma, osteosarcoma, alveolar soft part sarcoma,angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans,desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma,extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma,gastrointestinal stromal tumor (GIST), hemangiopericytoma,hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheathtumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, orundifferentiated pleomorphic sarcoma.

In some embodiments, the disease or disorder is mesothelioma oradrenocarcinoma. In some embodiments, the disease or disorder ismesothelioma. In some embodiments, the disease or disorder isadrenocarcinoma.

MDSC (myeloid-derived suppressor cells) are a heterogenous group ofimmune cells from the myeloid lineage (a family of cells that originatefrom bone marrow stem cells). MDSCs strongly expand in pathologicalsituations such as chronic infections and cancer, as a result of analtered haematopoiesis. MDSCs are discriminated from other myeloid celltypes in which they possess strong immunosuppressive activities ratherthan immunostimulatory properties. Similar to other myeloid cells, MDSCsinteract with other immune cell types including T cells, dendriticcells, macrophages and natural killer cells to regulate their functions.In some embodiments, the compounds, etc. described herein can be used inmethods related to cancer tissue (e.g., tumors) with high infiltrationof MDSCs, including Solid tumors with high basal level of macrophageand/or MDSC infiltration.

In some embodiments, the compounds of the disclosure can be used intreating pulmonary inflammation, including bleomycin-induced pulmonaryfibrosis and injury related to adenosine deaminase deficiency (Baraldi,et al., Chem. Rev., 2008, 108, 238-263).

In some embodiments, the compounds of the disclosure can be used as atreatment for inflammatory disease such as allergic reactions (e.g., A2Badenosine receptor dependent allergic reactions) and other adenosinereceptor dependent immune reactions. Further inflammatory diseases thatcan be treated by compounds of the disclosure include respiratorydisorders, sepsis, reperfusion injury, and thrombosis.

In some embodiments, the compounds of the disclosure can be used as atreatment for cardiovascular disease such as coronary artery disease(myocardial infarction, angina pectoris, heart failure), cerebrovasculardisease (stroke, transient ischemic attack), peripheral artery disease,and aortic atherosclerosis and aneurysm. Atherosclerosis is anunderlying etiologic factor in many types of cardiovascular disease.Atherosclerosis begins in adolescence with fatty streaks, which progressto plaques in adulthood and finally results in thrombotic events thatcause occlusion of vessels leading to clinically significant morbidityand mortality. Antagonists to the A2B adenosine receptor and A2Aadenosine receptor may be beneficial in preventing atheroscleroticplaque formation (Eisenstein, A. et al., J. Cell Physiol., 2015,230(12), 2891-2897).

In some embodiments, the compounds of the disclosure can be used as atreatment for disorders in motor activity; deficiency caused bydegeneration of the striatonigral dopamine system; and Parkinson'sdisease; some of the motivational symptoms of depression (Collins, L. E.et al. Pharmacol. Biochem. Behav., 2012, 100, 498-505).

In some embodiments, the compounds of the disclosure can be used as atreatment for diabetes and related disorders, such as insulinresistance. Diabetes affects the production of adenosine and theexpression of A2B adenosine receptors (A2BRs) that stimulate IL-6 andCRP production, insulin resistance, and the association between A_(2B)Rgene single-nucleotide polymorphisms (ADORA2B SNPs) and inflammatorymarkers. The increased A2BR signaling in diabetes may increase insulinresistance in part by elevating pro-inflammatory mediators. SelectiveA2BR blockers may be useful to treat insulin resistance (Figler, R. A.et al. Diabetes, 2011, 60 (2), 669-679).

It is believed that compounds provided herein, e.g., compounds ofFormula (I), or any of the embodiments thereof, may possess satisfactorypharmacological profile and promising biopharmaceutical properties, suchas toxicological profile, metabolism and pharmacokinetic properties,solubility, and permeability. It will be understood that determinationof appropriate biopharmaceutical properties is within the knowledge of aperson skilled in the art, e.g., determination of cytotoxicity in cellsor inhibition of certain targets or channels to determine potentialtoxicity.

The terms “individual” or “patient”, used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies I. Immune-Checkpoint Therapies

In some embodiments, A2A and A2B dual inhibitors provided herein can beused in combination with one or more immune checkpoint inhibitors forthe treatment of cancer as described herein. In one embodiment, thecombination with one or more immune checkpoint inhibitors as describedherein can be used for the treatment of melanoma. Compounds of thepresent disclosure can be used in combination with one or more immunecheckpoint inhibitors. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD20, CD28, CD40,CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA,CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, thecompounds of the disclosure provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the A2A and A2B dual inhibitors provided herein canbe used in combination with one or more agonists of immune checkpointmolecules, e.g., OX40, CD27, OX40, GITR, and CD137 (also known as4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB 122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g.urelumab or utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is INCB086550.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3, tumor specific antigens (e.g., CD70) or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO 1,TDO, or arginase. Examples of IDO 1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors or one or moretherapies for the treatment of diseases, such as cancer. Examples ofdiseases and indications treatable with combination therapies includethose as described herein.

The compounds of the present disclosure can be used in combination withone or more additional pharmaceutical agents such as, for example,chemotherapeutics, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF and FAK kinase inhibitors. The one ormore additional pharmaceutical agents can be administered to a patientsimultaneously or sequentially.

For example, the compounds as disclosed herein can be combined with oneor more inhibitors of the following kinases for the treatment of cancerand other diseases or disorders described herein: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS—R, IGF-1R, IR—R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. Non-limiting examples of inhibitors that can becombined with the compounds of the present disclosure for treatment ofcancer and other diseases and disorders described herein include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919,or BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Piminhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor,bromo and extra terminal family members inhibitors (for example,bromodomain inhibitors or BET inhibitors such as INCB54329 andINCB57643) and an adenosine receptor antagonist or combinations thereof.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Smll,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumortargeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, Toll receptor agonists, STING agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, daunorubicin,decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone propionate, eculizumab, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, rucaparib, streptozocin, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat, niraparib, veliparib, talazoparib, and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present disclosure with anadditional agent.

In some embodiments, the compounds of the disclosure can be used incombination with an inhibitor of JAK or PI3Kδ.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating A2A and/or A2B receptors intissue samples, including human, and for identifying A2A and/or A2Bantagonists by inhibition binding of a labeled compound. Substitution ofone or more of the atoms of the compounds of the present disclosure canalso be useful in generating differentiated ADME (Adsorption,Distribution, Metabolism and Excretion.) Accordingly, the presentdisclosure includes adenosine receptor (e.g., A2A and/or A2B) assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsin any of the disclosed Formulas, e.g., Formula (I), can beperdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuteriumatoms. In some embodiments, all of the hydrogen atoms in a compound canbe replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of any “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₆alkyl-”, “alkylene”, “alkenylene” and “alkynylene” linking groups, asdescribed herein, are each optionally replaced by a deuterium atom.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an adenosine receptor by monitoringits concentration variation when contacting with the adenosine receptor,through tracking of the labeling. For example, a test compound (labeled)can be evaluated for its ability to reduce binding of another compoundwhich is known to bind to a an adenosine receptor (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the adenosine receptor directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of adenosine receptor-associateddiseases or disorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of an adenosine receptor (e.g., A2A and/or A2B) accordingto at least one assay described herein.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5m, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 m, 30×100 mm or WatersXBridge™ C₁₈ 5 m, 30×100 mm column, eluting with mobile phase A: 0.1%TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile;the flow rate was 60 mL/minute, the separating gradient was optimizedfor each compound using the Compound Specific Method Optimizationprotocol as described in the literature (see e.g. “Preparative LCMSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

pH=10 purifications: Waters XBridge™ C₁₈ 5 m, 30×100 mm column, elutingwith mobile phase A: 0.1% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 60 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)).

Example 1.4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-ethyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

Step 1: Diethyl1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate

To a solution of diethyl 1H-pyrazole-3,5-dicarboxylate (12.9 g, 60.8mmol), 3-(2-bromoacetyl)benzonitrile (13.62 g, 60.8 mmol) in acetone(253 mL) was added potassium carbonate (9.24 g, 66.9 mmol). The mixturewas stirred at room temperature (rt or RT) for 12 h. The reactionmixture was concentrated and the residue was taken up in water anddichloromethane (DCM). The organic phase was washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified withflash chromatography to give the desired product as a white solid (21.6g, 100%). LC-MS calculated for C₁₈H₁₈N₃O₅ (M+H)⁺: m/z=356.1; found356.1.

Step 2: Ethyl6-(3-cyanophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate

Diethyl 1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(21.6 g, 60.8 mmol) was dissolved in acetic acid (260 mL), and ammoniumacetate (46.9 g, 608 mmol) was added. The mixture was stirred at 110° C.for 36 h. After cooling to rt, the mixture was diluted with water, theprecipitate was collected via filtration, washed with water, and driedto give the product. LC-MS calculated for C₁₆H₁₃N₄O₃ (M+H)⁺: m/z=309.1;found 309.1.

Step 3: Ethyl4-chloro-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate

A mixture of ethyl6-(3-cyanophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate(15.8 g, 51.2 mmol) and POCl₃ (96 mL, 1025 mmol) was heated at 110° C.for 4 h. After cooling to rt, the mixture was slowly added to a flaskcontaining ice and sodium bicarbonate. The resulting precipitate wascollected, washed with water, and dried to give the product (15.8 g,94%). LC-MS calculated for C₁₆H₁₂ClN₄O₂(M+H)⁺: m/z=327.1; found 327.1.

Step 4. Ethyl6-(3-cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylate

A microwave vial was charged with ethyl4-chloro-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate (1.22 g,3.73 mmol), (2,4-dimethoxyphenyl)methanamine (0.749 g, 4.48 mmol),N,N-diisopropylethylamine (DIEA, 1.304 mL, 7.47 mmol) and butan-1-ol(13.0 mL). The mixture was heated at 180° C. for 30 min in microwavereactor. The mixture was diluted with water, and the resultingprecipitate was collected via filtration, washed with water, and driedto give the product (1.5 g, 88%). LC-MS calculated for C₂₅H₂₄N₅O₄(M+H)⁺: m/z=458.2; found 458.2.

Step 5:6-(3-Cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylicAcid

A mixture of ethyl6-(3-cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylate(1.35 g, 2.95 mmol), sodium hydroxide (5.90 mL, 5.90 mmol), andacetonitrile (20 mL) was stirred at room temperature for 2 h, Thereaction was diluted with 1 N HCl (6 mL). The precipitate was collectedvia filtration, washed with water, and dried to give the product (1.0 g,79%). LC-MS calculated for C₂₃H₂₀N₅O₄ (M+H)⁺: m/z=430.1; found 430.1.

Step 6.4-Amino-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide

To a vial was added6-(3-cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylicacid (0.5 g, 1.164 mmol), PyBOP (0.727 g, 1.397 mmol), anddimethylformamide (DMF, 1.0 mL), followed by 2.0 M ethanamine intetrahydrofuran (THF, 1.164 mL, 2.329 mmol) andN,N-diisopropylethylamine (1.017 mL, 5.82 mmol). After stirring at roomtemperature (rt) for 2 h, the reaction mixture was diluted with waterand DCM. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The crude was treated with trifluoroacetic acid (TFA, 0.5mL) and heated at 90° C. for 30 min. After removing the solvent, theresulting precipitate was washed with water and ethyl acetate to givethe desired product as white solid (0.32 g, 90%). LC-MS calculated forC₁₆H₁₅N₆O (M+H)⁺: m/z=307.1; found 307.1.

Step 7.4-Amino-7-bromo-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide

To a solution of4-amino-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide(747 mg, 2.439 mmol) in DCM (5 mL) and DMF (1.250 mL) was addedN-bromosuccinimide (NBS, 421 mg, 2.365 mmol). The resulting mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith DCM and water. The organic layer was dried over Na₂SO₄, filtered,and concentrated. The precipitate was collected and washed with ethylacetate to give the desired product as white solid (0.75 g, 80%). LC-MScalculated for C₁₆H₁₄BrN₆O (M+H)⁺: m/z=385.0, 387.0; found 385.0, 387.0.

Step 8.4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-ethyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

A mixture of4-amino-7-bromo-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide(14 mg, 0.036 mmol),1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.69 mg, 0.044 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol) and tripotassium phosphate hydrate (18.41 mg,0.080 mmol) in 1,4-dioxane (0.6 mL)/water (0.200 mL) was stirred at 80°C. for 1 h. The residue was dissolved in methanol and 1 N HCl andpurified with prep-LCMS (pH 2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₂₁H₂₁N₈O (M+H)⁺:m/z=401.2; found 401.2. ¹H NMR (600 MHz, DMSO) δ 8.07 (t, J=6.0 Hz, 1H),7.80-7.73 (m, 3H), 7.73-7.70 (m, 1H), 7.56-7.46 (m, 4H), 6.32 (d, J=1.8Hz, 1H), 3.87 (m, 1H), 3.75 (m, 1H), 3.27 (m, 2H), 1.16 (t, J=7.2 Hz,3H), 1.08 (t, J=7.1 Hz, 3H).

Example 2.4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-propyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

The title compound was prepared using similar procedures as describedfor Example 1, with1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inStep 8. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₂H₂₃N₈O (M+H)⁺: m/z=415.2; found 415.2.

Example 3.4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

The title compound was prepared using similar procedures as describedfor Example 1 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onereplacing1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inStep 8. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₂H₂₀N₇O₂ (M+H)⁺: m/z=414.2; found 414.2.

Example 4.4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

A mixture of4-amino-7-bromo-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide(Example 1, Step 7; 10 mg, 0.026 mmol), 4-(tributylstannyl)pyrimidine(14.4 mg, 0.039 mmol), and copper(I) chloride (3.1 mg, 0.031 mmol),lithium chloride (1.3 mg, 0.031 mmol) andtetrakis(triphenylphosphine)palladium(0) (3.0 mg, 2.60 μmol) in THF (1.0mL) was first purged with N₂, and then heated and stirred at 90° C. for2 h. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt (4.2 mg,42%). LC-MS calculated for C₂₀H₁₇N₈O (M+H)⁺: m/z=385.1; found 385.1.

Example 5.4-Amino-6-(3-cyanophenyl)-7-(1,1-difluoroethyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide

To a vial was added4-amino-6-(3-cyanophenyl)-N-ethylpyrazolo[1,5-a]pyrazine-2-carboxamide(Example 1, Step 6; 20.0 mg, 0.065 mmol), sodium1,1-difluoroethane-1-sulfinate (59.6 mg, 0.392 mmol), diethyl carbonate(2.0 mL), water (1.3 mL) and tert-butyl hydroperoxide (0.090 mL, 0.653mmol). The resulting mixture was heated at 90° C. for 3 h. The reactionmixture was purified by prep-LCMS (pH=2, acetonitrile/water+TFA) to givethe desired product as TFA salt (5.6 mg, 23%). LC-MS calculated forC₁₈H₁₇F₂N₆O (M+H)⁺: m/z=371.1; found 371.1.

Example 6.4-Amino-6-(3-cyanophenyl)-N-ethyl-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrazine-2-carboxamide

The title compound was prepared using similar procedures as describedfor Example 5 with sodium 1-(trifluoromethyl)cyclopropane-1-sulfinatereplacing sodium 1,1-difluoroethane-1-sulfinate. The reaction mixturewas purified by prep-LCMS (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₂₀H₁₈F₃N₆O (M+H)⁺:m/z=415.1; found 415.1.

Example 7.3-(4-Amino-2-(azetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1. Ethyl4-amino-7-bromo-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate

To a solution of ethyl6-(3-cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylate(Example 1, Step 4; 8.35 g, 18.26 mmol) was treated with TFA (20 mL) andheated at 90° C. for 30 min. After removing the solvent, the resultingprecipitate was washed with water and ethyl acetate. The crude productwas dissolved in DCM (73.0 mL) and DMF (18.26 mL), to this solution NBS(3.15 g, 17.71 mmol) was added. The resulting mixture was stirred atroom temperature for 1 h. The reaction mixture was diluted with DCM andwater. The precipitate was collected vial filtration and washed withwater to give the desired product as a white solid (5.6 g, 79%). LC-MScalculated for C₁₆H₁₃BrN₅O₂ (M+H)⁺: m/z=386.0; found 386.0.

Step 2. Ethyl4-amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

A mixture of ethyl4-amino-7-bromo-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate(904 mg, 2.341 mmol), 4-(tributylstannyl)pyrimidine (1.3 g, 3.51 mmol),copper(I) chloride (278 mg, 2.81 mmol), lithium chloride (119 mg, 2.81mmol), and tetrakis(triphenylphosphine)palladium(0) (270 mg, 0.234 mmol)in THF (15 mL) was first purged with N₂, and then heated and stirred at90° C. for 2 h. The reaction was diluted with ethyl acetate and water,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified with flash chromatography to givethe desired product (0.34 g, 38%). LC-MS calculated for C₂₀H₁₆N₇O₂(M+H)⁺: m/z=386.1; found 386.2.

Step 3.4-Amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicAcid

A mixture of ethyl4-amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(340 mg, 0.882 mmol), 1.0 M sodium hydroxide (4.41 mL, 4.41 mmol),acetonitrile (10 mL), and THF (5.00 mL) was stirred at room temperaturefor 2 h. The reaction was quenched with 1 N HCl to pH 4. After removingmost of the organic solvent, the precipitate was collected viafiltration, washed with water, and dried under vacuum to give thedesired product as a white solid (295 mg, 94%). LC-MS calculated forC₁₈H₁₂N₇O₂ (M+H)⁺: m/z=358.1; found 358.1.

Step 4.3-(4-Amino-2-(azetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of4-amino-6-(3-cyanophenyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid (8.0 mg, 0.022 mmol) and HATU (8.51 mg, 0.022 mmol) inN,N-dimethylformamide (1.0 mL), was added azetidine (3.02 μl, 0.045mmol) and DIEA (7.82 μl, 0.045 mmol). After stirring at rt for 2 h, Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt (2.5 mg,28%). LC-MS calculated for C₂₁H₁₇N₈O (M+H)⁺: m/z=397.1; found 397.1. ¹HNMR (500 MHz, DMSO) δ 9.11 (m, 1H), 8.94 (d, J=5.2 Hz, 1H), 7.96-7.90(m, 2H), 7.79-7.73 (m, 3H), 7.55 (m, 2H), 7.47 (t, J=7.7 Hz, 1H), 4.29(t, J=7.7 Hz, 2H), 4.03 (t, J=7.7 Hz, 2H), 2.24 (m, 2H).

Example 8.3-(4-Amino-7-(pyrimidin-4-yl)-2-(pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 7 with pyrrolidine replacing azetidine in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₂H₁₉N₈O (M+H)⁺: m/z=411.2; found 411.2.

Example 9.3-(4-Amino-2-(piperidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 7 with piperidine replacing azetidine in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₃H₂₁N₈O (M+H)⁺: m/z=425.2; found 425.3.

Example 10.4-Amino-6-(3-cyanophenyl)-N,N-diethyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

The title compound was prepared using similar procedures as describedfor Example 7 with diethylamine replacing azetidine in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₂H₂₁N₈O (M+H)⁺: m/z=413.2; found 413.2. ¹H NMR (500MHz, DMSO) δ 9.16 (d, J=1.3 Hz, 1H), 8.93 (d, J=5.2 Hz, 1H), 8.02-7.95(m, 2H), 7.87 (m, 1H), 7.83-7.75 (m, 2H), 7.58-7.38 (m, 3H), 3.50 (q,J=6.8 Hz, 2H), 3.41 (q, J=7.0 Hz, 2H), 1.12 (t, J=7.0 Hz, 3H), 1.00 (t,J=6.9 Hz, 3H).

Example 11.4-Amino-6-(3-cyanophenyl)-N-ethyl-N-methyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxamide

The title compound was prepared using similar procedures as describedfor Example 7 with N-methylethanamine replacing azetidine in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₁H₁₉N₈O (M+H)⁺: m/z=399.2; found 399.2.

Example 12.3-(4-Amino-2-(3-hydroxyazetidine-1-carbonyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 7 with azetidin-3-ol replacing azetidine in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₁H₁₇N₈O₂ (M+H)⁺: m/z=413.1; found 413.1.

Example 13.3-(4-Amino-2-(azetidin-1-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1.3-(4-Amino-7-bromo-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of ethyl4-amino-7-bromo-6-(3-cyanophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate(Example 7, Step 1; 0.547 g, 1.416 mmol) in CH₂Cl₂ (7.08 mL) and THF(7.08 mL) was added 1.0 M DIBAL-H in THF (4.25 mL, 4.25 mmol) at 0° C.The resulting mixture was warmed to room temperature and stirredovernight. The reaction was diluted with DCM and 1 N NaOH solution. Theorganic layer was separated and dried over Na₂SO₄, filtered, andconcentrated. The crude was used in the next step without purification.LC-MS calculated for C₁₄H₁₁BrN₅O (M+H)⁺: m/z=344.0; found 344.0.

Step 2.3-(4-Amino-2-(hydroxymethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(487 mg, 1.415 mmol), 4-(tributylstannyl)pyrimidine (575 mg, 1.556mmol), copper(I) chloride (168 mg, 1.698 mmol), lithium chloride (72.0mg, 1.698 mmol) and tetrakis(triphenylphosphine)palladium(0) (164 mg,0.141 mmol) in THF (12 mL) was first purged with N₂, and then heated andstirred at 90° C. for 2 h. The reaction was diluted with ethyl acetateand water, the aqueous layer was extracted with ethyl acetate once. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified with flashchromatography to give the desired product (0.16 g, 34% for 2 steps).LC-MS calculated for C₁₈H₁₄N₇O (M+H)⁺: m/z=344.1; found 344.1.

Step 3.3-(4-Amino-2-formyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-2-(hydroxymethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(160 mg, 0.466 mmol), Dess-Martin periodinane (237 mg, 0.559 mmol), andCH₂Cl₂ (4660 μL) was stirred at room temperature for 2 h. The reactionwas diluted with DCM and saturated NaHCO₃ solution. After stirring for30 min, the organic layer was separated and dried over Na₂SO₄, filtered,and concentrated. The crude was used in the next step withoutpurification. LC-MS calculated for C₁₈H₁₂N₇O (M+H)⁺: m/z=342.1; found342.1.

Step 4.3-(4-Amino-2-(azetidin-1-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a mixture of3-(4-amino-2-formyl-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.029 mmol) and azetidine (3.35 mg, 0.059 mmol) in DCM (1 mL)was added sodium triacetoxyborohydride (12.4 mg, 0.059 mmol). Afterstirring at room temperature for 2.5 h, solvent was removed in vacuo.The resulting residue was dissolved in methanol and 1 N HCl (1 N) andpurified with prep-LCMS (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₂₁H₁₉N₈(M+H)⁺:m/z=383.2; found 383.2.

Example 14.Ethyl(8-amino-6-(3-cyanophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate

Step 1. tert-Butyl((mesitylsulfonyl)oxy)carbamate

To a solution of 2,4,6-trimethylbenzenesulfonyl chloride (9.10 g, 41.6mmol) and tert-butyl N-hydroxycarbamate (5.54 g, 41.6 mmol) in methyltert-butyl ether (MTBE, 90 mL) was added triethylamine (TEA, 6.09 mL,43.7 mmol) dropwise while stirring at 0° C. The resulting suspension wasstirred at 0° C. for an additional 30 min and then warmed to ambienttemperature. The reaction was then diluted with water (90 mL) andadjusted to pH 4 with 1 N HCl. The organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated to give the desiredproduct. LC-MS calculated for C₁₄H₂₂NO₅S (M+H)⁺: m/z=316.1; found 316.1.

Step 2. O-(Mesitylsulfonyl)hydroxylamine

To TFA (37.7 mL, 490 mmol) at 0° C. was slowly added tert-butyl((mesitylsulfonyl)oxy)carbamate (12.56 g, 39.8 mmol). The reactionmixture was stirred at 0° C. for 1.5 h and then quenched with thesequential addition of crushed ice and water. The resulting whitesuspension was vigorously stirred at ambient temperature for 5 min.Without allowing the filter cake to run dry, the solids were collectedby careful vacuum filtration followed by subsequent rinsing with wateruntil the filtrate reached pH 6. The wet filtrate was taken up in DCMand the resulting biphasic solution was separated. The DCM layer wasdried over MgSO₄ for 30 min and then filtered and rinsed with DCM toprovide the compound as a solution. LC-MS calculated for C₉H₁₄NO₃S(M+H)⁺: m/z=216.1; found 216.1.

Step 3. 1,2-Diamino-3,5-dibromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (2.468 g, 11.47 mmol)in CH₂Cl₂ (50 mL) was added 3,5-dibromopyrazin-2-amine (2.90 g, 11.47mmol), and the resulting solution was stirred at ambient temperatureovernight. The precipitate was collected vial filtration and dried undervacuum. LC-MS calculated for C₄H₅Br₂N₄(M)⁺: m/z=266.9; found 266.9.

Step 4. Ethyl(6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazin-2-yl) carbamate

To a suspension of 1,2-diamino-3,5-dibromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (190 mg, 0.406 mmol) in DCM (1.0 mL) andN,N-dimethylformamide (1 mL) was added O-ethyl carbonisothiocyanatidate(52.7 μl, 0.446 mmol). The resulting mixture as stirred at roomtemperature for 3 h. The reaction mixture was diluted with DCM andwater. The organic layer was separated and dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified with flashchromatography to give the desired product (10 mg, 8%) LC-MS calculatedfor C₈H₈Br₂N₅O₂ (M+H)⁺: m/z=365.9; found 365.8.

Step 5.Ethyl(6-bromo-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate

To a mixture ofethyl(6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate (10 mg,0.027 mmol) and (2,4-dimethoxyphenyl)methanamine (4.58 mg, 0.027 mmol)in DCM (1 mL) was added DIEA (9.57 μl, 0.055 mmol). After stirring at40° C. for 2.5 h, the solvent was removed in vacuo. The residue waspurified with flash chromatography to give the desired product (6.0 mg,49%). LC-MS calculated for C17H₂₀BrN₆O₄(M+H)⁺: m/z=451.1, 453.1; found451.1, 453.1.

Step 6.Ethyl(6-(3-cyanophenyl)-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate

A mixture ofethyl(6-bromo-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate(6.0 mg, 0.013 mmol), (3-cyanophenyl)boronic acid (1.954 mg, 0.013mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.046 mg, 1.330 μmol) and tripotassium phosphate hydrate (6.74mg, 0.029 mmol) in 1,4-dioxane (0.6 mL)/water (0.200 mL) was stirred at70° C. for 1 h. The resulting residue was dissolved in methanol and 1 NHCl and purified with prep-LCMS (pH 2) to give the desired product aswhite solid (4.2 mg, 66%). LC-MS calculated for C₂₄H₂₄N₇O₄ (M+H)⁺:m/z=474.2; found 474.2.

Step 7.Ethyl(8-amino-6-(3-cyanophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate

A mixture ofethyl(6-(3-cyanophenyl)-8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate(6.3 mg, 0.013 mmol) and trifluoroacetic acid (0.3 mL) was stirred at90° C. for 30 min. The volatiles were removed and the resulting residuewas diluted with methanol and purified with prep-LCMS (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt (0.3 mg,7%). LC-MS calculated for C₁₅H₁₄N₇O₂ (M+H)⁺: m/z=324.1; found 324.1.

Example 15.3-(8-Amino-5-(6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1.6-Bromo-N-(2,4-dimethoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

A vial was charged with 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (720mg, 2.59 mmol), (2,4-dimethoxyphenyl)methanamine (433 mg, 2.59 mmol),DIEA (679 μl, 3.89 mmol), 2-propanol (6 mL), and N,N-dimethylformamide(6 mL). The mixture was heated at 90° C. for 2 h and then diluted withwater. The resulting precipitate was collected vial filtration (0.94 g,100%). LC-MS calculated for C₁₄H₁₅BrN₅O₂(M+H)⁺: m/z=364.0, 366.0; found364.0, 366.0.

Step 2.3-(8-((2,4-Dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of6-bromo-N-(2,4-dimethoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(0.94 g, 2.58 mmol), (3-cyanophenyl)boronic acid (0.417 g, 2.84 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.203 g, 0.258 mmol) and tripotassium phosphate hydrate (1.486 g,6.45 mmol) in 1,4-dioxane (9.68 mL)/water (3.23 mL) was stirred at 70°C. for 1 h. After cooling to rt, the mixture was diluted with water. Theresulting precipitate was collected via filtration (0.7 g, 70%). LC-MScalculated for C₂₁H₁₉N₆O₂ (M+H)⁺: m/z=387.1; found 387.1.

Step 3. 3-(8-Amino-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-((2,4-dimethoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.70 g, 1.812 mmol) and trifluoroacetic acid (4.19 mL, 54.3 mmol) washeated at 90° C. for 30 min. The volatiles were removed in vacuo. Theresulting solid was washed with water and ethyl acetate and dried undervacuum (0.35 g, 82%). LC-MS calculated for C₁₂H9N₆(M+H)⁺: m/z=237.1;found 237.1.

Step 4.3-(8-Amino-5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-amino-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile (129 mg,0.546 mmol) in DCM (5 mL) and DMF (1.250 mL) was added NBS (94 mg, 0.530mmol). The resulting mixture was stirred at room temperature for 1 h.The reaction mixture was diluted with DCM and water. The precipitate wascollected via filtration and washed with water and ethyl acetate (135mg, 78%) LC-MS calculated for C₁₂H₈BrN₆ (M+H)⁺: m/z=315.0, 317.0; found315.0, 317.0.

Step 5.3-(8-Amino-5-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile (20mg, 0.063 mmol), (6-methoxypyridin-3-yl)boronic acid (9.71 mg, 0.063mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (5.0 mg, 6.35 μmol), and tripotassium phosphate hydrate (32.2 mg,0.140 mmol) in 1,4-dioxane (0.6 mL)/water (0.200 mL) was stirred at 70°C. for 1 h. The residue was dissolved in methanol and 1 N HCl andpurified with prep-LCMS (pH=2, acetonitrile/water+TFA) to give thedesired product as white solid (12 mg, 55%). LC-MS calculated forC₁₈H₁₄N₇O (M+H)⁺: m/z=344.1; found 344.1.

Step 6.3-(8-Amino-5-(6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-5-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.029 mmol), potassium iodide (14.50 mg, 0.087 mmol), and aceticacid (1.0 mL) was heated at 90° C. for 1 h. The mixture was diluted withmethanol and purified with prep-LCMS (pH=2, acetonitrile/water+TFA) togive the desired product as TFA salt (3.5 mg, 37%). LC-MS calculated forC₁₇H₁₂N₇O (M+H)⁺: m/z=330.1; found 330.1.

Example 16.3-(4-Amino-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(4-(2,4-Dimethoxybenzylamino)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of ethyl6-(3-cyanophenyl)-4-((2,4-dimethoxybenzyl)amino)pyrazolo[1,5-a]pyrazine-2-carboxylate(Example 1, Step 4; 4.00 g, 8.74 mmol) in THF (200 mL) was addeddiisobutylaluminum hydride (1.0 M toluene solution, 35.0 mL, 35.0 mmol)at −78° C. The reaction mixture was warmed to rt and stirred at rt for30 min. The reaction mixture was quenched by adding 300 mL of saturatedRochelle's salt water solution. The resulting mixture was stirred at rtfor 1 h, which was then concentrated and the residue was extracted withDCM. The organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified with flashchromatography to give the desired product as white solid (2.1 g, 58%).LC-MS calculated for C₂₃H₂₂N₅O₃ (M+H)⁺: m/z=416.1; found 416.2.

Step 2:3-(2-(Bromomethyl)-4-(2,4-dimethoxybenzylamino)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(4-(2,4-Dimethoxybenzylamino)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(3.0 g, 7.22 mmol) was dissolved in DCM (200 mL), and PBr₃ (1.4 mL,14.44 mmol) was added. The mixture was stirred at rt for 5 h. Aftercompletion, the reaction was quenched by adding sat. NaHCO₃, the mixturewas then extracted with DCM. The organic phase was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedwith flash chromatography to give the desired product as white solid(2.4 g, 69%). LC-MS calculated for C23H₂₁BrN₅O₂ (M+H)⁺: m/z=478.1; found478.1.

Step 3:3-(4-(2,4-Dimethoxybenzylamino)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-(bromomethyl)-4-(2,4-dimethoxybenzylamino)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(700 mg, 1.46 mmol), CuI (55.7 mg, 0.293 mmol), CsF (445 mg, 2.93 mmol),tetrakis(triphenylphosphine)palladium(0) (169 mg, 0.146 mmol), and2-(tributylstannyl)pyridine (646 mg, 1.756 mmol) in 1,4-dioxane (2 mL)was heated at 140° C. for 1 h in a microwave reactor. The reaction wasdiluted with water and extracted with DCM. The organic phase was washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The residuewas purified with flash chromatography to give the desired product aswhite solid (428 mg, 62%). LC-MS calculated for C₂₈H₂₅N₆O₂ (M+H)⁺:m/z=477.2; found 477.2.

Step 4.3-(4-Amino-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A reaction vial was charged with3-(4-(2,4-dimethoxybenzylamino)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(428 mg, 0.9 mmol) and TFA (1 mL). The mixture was heated at 70° C. for20 min. The mixture was diluted with water and quenched with sat.NaHCO₃. The mixture was extracted with DCM. The organic phase was washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The residuewas purified with flash chromatography to give the desired product as alight yellow solid (260 mg, 89%). LC-MS calculated for C₁₉H₁₅N₆(M+H)⁺:m/z=327.1; found 327.2.

Example 17.3-(4-Amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(4-Amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(4-amino-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 16, Step 4; 260 mg, 0.8 mmol) in DMF (2 mL) was added a DMF(0.5 mL) solution of N-bromosuccinimide (122 mg, 0.68 mmol) dropwise at0° C. The resulting mixture was stirred at 0° C. for 10 min. Thereaction mixture was diluted with water. The mixture was extracted withDCM. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified with flashchromatography to give the desired product as a light yellow oil (202mg, 62%). LC-MS calculated for C₁₉H₁₄BrN₆ (M+H)⁺: m/z=405.0; found405.1.

Step 2.3-(4-Amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(15 mg, 0.037 mmol), CuI (1.4 mg, 0.007 mmol), CsF (11 mg, 0.074 mmol),tetrakis(triphenylphosphine)palladium(0) (4.2 mg, 0.004 mmol), and4-(tributylstannyl)pyrimidine (16.4 mg, 0.044 mmol) in 1,4-dioxane washeated at 140° C. for 1 h in a microwave reactor. The reaction mixturewas concentrated under vacuum and the resulting residue was dissolved inmethanol, added a few drops of TFA, and purified with prep-LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₃H₁₇N₈(M+H)⁺: m/z=405.2 found 405.2.

Example 18.3-(4-Amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 17, Step 1; 15 mg, 0.037 mmol),1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.69 mg, 0.044 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol) and Cs₂CO₃ (23.2 mg, 0.071 mmol) in1,4-dioxane (1 mL)/water (0.200 mL) was stirred at 90° C. for 1 h. Thereaction mixture was concentrated under vacuum and the resulting residuewas dissolved in methanol and purified with prep-LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₄H₂₁N₈(M+H)⁺: m/z=421.2; found 421.2.

Example 19.4-(4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxamide

Step 1.3-(4-(2,4-Dimethoxybenzylamino)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-(bromomethyl)-4-(2,4-dimethoxybenzylamino)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 16, Step 2; 200 mg, 0.42 mmol), (2-fluorophenyl)boronic acid(70.2 mg, 0.502 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (32.9 mg, 0.042 mmol) and Cs₂CO₃ (272 mg, 0.836 mmol) in1,4-dioxane (2 mL)/water (0.2 mL) was stirred at 90° C. for 3 h. Thereaction was diluted by water and extracted with DCM. The organic phasewas washed with brine, dried over Na₂SO₄, filtered, and concentrated.The residue was purified with flash chromatography to give the desiredproduct as white solid (157 mg, 76%). LC-MS calculated for C₂₉H₂₅FN₅O₂(M+H)⁺: m/z=494.2; found 494.1.

Step 2.3-(4-Amino-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a reaction vial was charged with3-(4-(2,4-dimethoxybenzylamino)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(157 mg, 0.32 mmol), TFA (1 mL). The mixture was heated at 70° C. for 20min. The mixture was diluted with water, and quenched with sat. NaHCO₃.The mixture was extracted with DCM. The organic phase was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified with flash chromatography to give the desired product as whitesolid (96 mg, 87%). LC-MS calculated for C₂₀H₁₅FN₅ (M+H)⁺: m/z=344.1;found 344.2.

Step 3.3-(4-Amino-7-bromo-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrileand3-(4-amino-3-bromo-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(4-amino-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(96 mg, 0.28 mmol) in DMF (1 mL) was added a DMF (0.5 mL) solution ofN-bromosuccinimide (39.8 mg, 0.22 mmol) dropwise at 0° C. The resultingmixture was stirred at 0° C. for 10 min. The reaction mixture wasdiluted with water and extracted with DCM. The organic phase was washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The residuewas purified with flash chromatography to give two regioisomers (101 mg,0.24 mmol 86%), which are used directly in the next step. LC-MScalculated for C₂₀H₁₄FBrN₅ (M+H)⁺: m/z=422.0; found 422.1.

Step 4.4-(4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxamide

A mixture of3-(4-amino-7-bromo-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile,3-(4-amino-3-bromo-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(15 mg, 0.037 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxamide(13.4 mg, 0.053 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol) and Cs₂CO₃ (23.2 mg, 0.071 mmol) in1,4-dioxane (0.6 mL)/water (0.200 mL) was stirred at 90° C. for 1 h. Thereaction was concentrated under vacuum and the residue was dissolved inmethanol and purified with prep-LCMS (pH 2, acetonitrile/water+TFA) togive two compounds. Compound with shorter retention time was assigned astitle compound as a TFA salt. LC-MS calculated for C₂₆H₂₃FN₇O (M+H)⁺:m/z=468.2; found 468.2.

Example 20.4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazine-7-carbonitrile

A mixture of3-(4-amino-7-bromo-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile,3-(4-amino-3-bromo-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(15 mg, 0.037 mmol) (Example 19, Step 3), zinc cyanide (8.3 mg, 0.071mmol), and tBuXPhos-Pd-G3 (2.8 mg, 3.6 μmol) in 1,4-dioxane (1 mL)/water(1 mL) was stirred at 100° C. for 4 h. The reaction mixture wasconcentrated under vacuum and the resulting residue was dissolved inmethanol and purified with prep-LCMS (pH 2, acetonitrile/water+TFA) togive two compounds. Compound with shorter retention time was assigned astitle compound as a TFA salt. LC-MS calculated for C₂₁H₁₄FN₆ (M+H)⁺:m/z=369.1; found 369.2.

Example 21.4-Amino-6-(3-cyanophenyl)-2-(2-fluorobenzyl)pyrazolo[1,5-a]pyrazine-3-carbonitrile

The title compound was prepared using same procedures as described forExample 20. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give two compounds. Compound with longerretention time was assigned as title compound as a TFA salt. LC-MScalculated for C₂₁H₁₄FN₆ (M+H)⁺: m/z=369.1; found 369.2.

Example 22.3-(4-Amino-7-bromo-2-((2-fluorophenyl)(hydroxy)methyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1.3-(4-Amino-7-bromo-2-formylpyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(4-amino-7-bromo-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 13, Step 1; 1.06 g, 3.1 mmol) in DCM (30 mL) was addedDess-Martin periodinane (1.44 g, 3.39 mmol). The resulting mixture wasstirred at room temperature for 30 min. The reaction mixture was dilutedwith sat. NaHCO₃. The organic phase was washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified with flashchromatography to give the desired product as white solid (0.64 g, 61%).LC-MS calculated for C₁₄H9BrN₅O (M+H)⁺: m/z=342.0; found 342.0.

Step 2. 3-(4-Amino-7-bromo-2-((2-fluorophenyl)(hydroxy)methyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a THF (20 mL) solution of 1-fluoro-2-iodobenzene (0.31 mL, 2.7 mmol)was added isopropylmagnesium bromide (0.8 mL, 2.3 mmol) in THF dropwiseat −20° C., and the solution was stirred for 1 h. Then to the solutionwas added a THF (2 mL) solution of3-(4-amino-7-bromo-2-formylpyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (228mg, 0.67 mmol). The mixture was stirred for 12 h while warming to roomtemperature. After completion, the reaction was quenched by adding sat.NH₄Cl. The aqueous phase was extracted with DCM, and the organic phasewas washed with brine, dried over Na₂SO₄, filtered, and concentrated.The residue was purified with flash chromatography to give the desiredproduct as white solid (0.18 g, 63%). LC-MS calculated for C₂₀H₁₄BrFN₅O(M+H)⁺: m/z=438.0; found 438.1.

Example 23.3-(4-Amino-2-((2-fluorophenyl)(hydroxy)methyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-((2-fluorophenyl)(hydroxy)methyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 22; 16.0 mg, 0.037 mmol), CuI (1.4 mg, 0.007 mmol), CsF (11.0mg, 0.074 mmol), tetrakis(triphenylphosphine)palladium(0) (4.2 mg, 0.004mmol), and 4-(tributylstannyl)pyrimidine (16.4 mg, 0.044 mmol) in1,4-dioxane was heated at 140° C. for 1 h in a microwave reactor. Thereaction mixture was concentrated under vacuum and the resulting residuewas dissolved in methanol, mixed with a few drops of TFA, and purifiedwith prep-LCMS (pH 2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₂₄H₁₇FN₇O (M+H)⁺: m/z=438.1found 438.2.

Example 24.3-(4-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1.3-(2-Chloro-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of methyl 3-chloro-1H-pyrazole-5-carboxylate (901 mg, 5.61mmol) and 3-(2-bromoacetyl)benzonitrile (1257 mg, 5.61 mmol) in acetone(253 mL) was added potassium carbonate (853 mg, 6.17 mmol). The mixturewas stirred at rt for 12 h. The reaction mixture was then concentratedand the resulting residue was taken up in water and DCM. The organicphase was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was dissolved in acetic acid (30 mL), andammonium acetate (4.7 g, 60.8 mmol) was added. The mixture was stirredat 110° C. for 36 h. After cooling to rt, the mixture was diluted withwater and the precipitate was collected via filtration and washed withwater to give the desired product as white solid. LC-MS calculated forC₁₃H₈ClN₄O (M+H)⁺: m/z=271.0; found 271.1.

Step 2. 3-(2,4-Dichloropyrazolo[1,5-a]pyrazin-6-yl)benzontrile

A mixture of3-(2-chloro-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(1.6 g, 5.9 mmol) and POCl₃ (2 mL, 20.1 mmol) was heated at 110° C.overnight. After cooling to rt, the mixture was added to a flaskcontaining ice. The resulting precipitate was collected and washed withwater to give the desired product as white solid. (1.18 g, 69%). LC-MScalculated for C₁₃H7Cl₂N₄(M+H)⁺: m/z=289.0; found 289.1.

Step 3. 3-(4-Amino-2-chloropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A microwave vial was charged with3-(2,4-dichloropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (1.4 g, 4.84mmol), (2,4-dimethoxyphenyl)methanamine (0.90 g, 5.4 mmol), DIEA (1.304mL, 7.47 mmol) and butan-1-ol (10 mL). The mixture was heated at 150° C.for 30 min in a microwave reactor. The mixture was diluted with water,and the resulting precipitate was collected via filtration. The solidwas then treated with TFA (10 mL) and heated at 70° C. for 30 min. Thereaction was then quenched with sat. NaHCO₃, and the resulting solid wascollected via filtration and washed with water to give the desiredproduct as a white solid (860 mg, 3.2 mmol, 67%). LC-MS calculated forC₁₃H₉ClN₅ (M+H)⁺: m/z=270.0; found 270.0.

Step 4.3-(4-Amino-7-bromo-2-chloropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(4-amino-2-chloropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (860 mg, 3.2mmol) in DMF (5 mL) was added NBS (570 mg, 3.2 mmol). The resultingmixture was stirred at room temperature for 30 min. The reaction mixturewas diluted with water. The resulting precipitate was collected andwashed with water to give the desired product as white solid (972 mg,88%). LC-MS calculated for C₁₃H₈ClBrN₅ (M+H)⁺: m/z=348.0; found 348.0.

Step 5.3-(4-Amino-2-chloro-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-chloropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile (100mg, 0.288 mmol), CuI (14 mg, 0.07 mmol), CsF (110 mg, 0.74 mmol),tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.04 mmol), and4-(tributylstannyl)pyrimidine (118 mg, 0.34 mmol) in 1,4-dioxane (3 mL)was heated at 140° C. for 1 h in a microwave reactor. The reactionmixture was concentrated under vacuum and the resulting residue waspurified using flash chromatography to give the desired product as whitesolid (52 mg, 52%). LC-MS calculated for C₁₇H₁₁ClN₇ (M+H)⁺: m/z=348.1;found 348.1.

Step 6.3-(4-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-2-chloro-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(13 mg, 0.037 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(8.4 mg, 0.04 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol), and Cs₂CO₃ (23.2 mg, 0.071 mmol) in1,4-dioxane (1 mL)/water (0.200 mL) was stirred at 90° C. for 1 h. Thereaction mixture was concentrated under vacuum and the resulting residuewas dissolved in methanol and purified with prep-LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₂H₁₈N₇O (M+H)⁺: m/z=396.2; found 396.1.

Example 25.3-(4-Amino-2-(phenylamino)-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(4-Amino-2-chloro-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-chloropyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 24 Step 4; 129 mg, 0.370 mmol), pyridin-4-ylboronic acid (45.5mg, 0.370 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (30.2 mg, 0.037 mmol), sodiumcarbonate (78 mg, 0.740 mmol) in 1,4-dioxane (1682 μL), and water (168μL) was purged with N₂ and heated at 95° C. for 5 h. The mixture wasthen concentrated and purified by silica gel chromatograph eluting with0 to 13% MeOH in DCM to afford the desired product. LCMS calculated forC₁₈H₁₂ClN₆ (M+H)⁺: 347.1; found 347.1.

Step 2:3-(4-Amino-2-(phenylamino)-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-2-chloro-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.029 mmol), aniline (8.06 mg, 0.087 mmol), cesium carbonate(18.79 mg, 0.058 mmol),chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.56 mg, 2.88 μmol) (XantPhos Pd G2) in 1,4-dioxane (144 μl) was purgedwith N₂ and heated at 95° C. for 1 h. The mixture was concentrated andpurified by preparative LCMS (pH 2, acetonitrile/water with TFA) toafford the desired product as TFA salt. LCMS calculated forC₂₄H₁₈N₇(M+H)⁺: 404.2; found 404.1.

Example 26.3-(4-Amino-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(11.34 mg, 0.014 mmol) was added to a mixture of3-(4-amino-2-chloro-7-(pyridin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 25, Step 1; 50 mg, 0.144 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(52.5 mg, 0.173 mmol), sodium carbonate (15.28 mg, 0.144 mmol) in1,4-dioxane (655 μl) and water (65.5 μl). The mixture was purged with N₂and heated at 90° C. for 2 h. The resulting mixture was concentrated andpurified by preparative LCMS (pH 2, acetonitrile/water with TFA) toafford the product as TFA salt. LCMS calculated for C₂₈H₂₆N₉(M+H)⁺:488.2; found 488.1.

Example 27.3-(8-Amino-2-(pyridin-2-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1: Methyl3-bromo-1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-1,2,4-triazole-5-carboxylate

To a solution of methyl 3-bromo-1H-1,2,4-triazole-5-carboxylate (5.0 g,24.3 mmol), 3-(2-bromoacetyl)benzonitrile (5.44 g, 24.3 mmol) in DMF(100 mL) was added potassium carbonate (3.35 g, 24.3 mmol). The reactionmixture was stirred at ambient temperature for 2 h. The reaction mixturewas then diluted with water and DCM. The organic layer was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresulting residue was purified via flash chromatography to give thedesired product as a white solid (5.2 g, 61%). LC-MS calculated forC₁₃H₁₀BrN₄O₃ (M+H)⁺: m/z=349.0; found 349.0.

Step 2:3-(2-Bromo-8-oxo-7,8-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Methyl3-bromo-1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-1,2,4-triazole-5-carboxylate(10.5 g, 30.1 mmol) was dissolved in acetic acid (100 mL), and ammoniumacetate (23.18 g, 301 mmol) was added. The mixture was stirred at 110°C. for 12 h. After cooling to room temperature, the reaction mixture wasdiluted with water. The resulting precipitate was collected viafiltration, washed with water, and dried under vacuum to afford theproduct (8.4 g, 88%). LC-MS calculated for C₁₂H₇BrN₅O (M+H)⁺: m/z=316.0;found 316.0.

Step 3:3-(2-Bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-bromo-8-oxo-7,8-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(8.4 g, 26.6 mmol) and POCl₃ (49.5 mL, 531 mmol) was stirred at 110° C.overnight. After cooling to room temperature, the reaction mixture wasslowly added to a flask containing ice and sodium bicarbonate. Theresulting precipitate was collected, washed with water, and dried toafford the product (8.8 g, 99%). LC-MS calculated for C₁₂H₆BrClN₅(M+H)⁺:m/z=333.9; found 334.0.

Step 4.3-(8-(Bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(8.99 g, 26.9 mmol), bis(4-methoxybenzyl)amine (10.37 g, 40.3 mmol), andDIPEA (9.4 mL, 53.7 mmol) in DMF (134 mL) was stirred at 85° C.overnight. The reaction mixture was cooled to room temperature, anddiluted with water. The resulting precipitate was collected viafiltration, and dried to afford the product (14.1 g, 94%). LC-MScalculated for C₂₈H₂₄BrN₆O₂(M+H)⁺: m/z=555.1; found 555.1.

Step 5:3-(8-(Bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of 2-methylpyridine (0.050 g, 0.540 mmol) in THF (0.5 mL)was added 2.5 M n-butyllithium (0.216 mL, 0.540 mmol) at −78° C. Theresulting solution was stirred at the same temperature for 1 h, before1.9 M zinc chloride in 2-methyltetrahydrofuran (0.284 mL, 0.540 mmol)was added, and the resulting mixture was stirred at room temperature for10 min.

A microwave vial charge with3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.15 g, 0.270 mmol), palladium acetate (1.1 mg, 4.7 μmol), and2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine(4.1 mg, 9.5 μmol) was evacuated under high vacuum and backfilled withnitrogen. THF (2.0 mL) and toluene (0.5 mL) was then added to thereaction vial. The mixture was cooled to 0° C. and the zinc reagentprepared from previous step was added slowly via a syringe. The reactionmixture was then stirred at 60° C. overnight, cooled to roomtemperature, and partitioned between ethylacetate and saturated NH₄Clsolution. The layers were separated and the aqueous layer was extractedwith ethylacetate. The combined organic layers were washed with waterand brine, dried over MgSO₄, and concentrated. The resulting residue waspurified via flash chromatography to afford the product (0.11 g, 71%).LC-MS calculated for C₃₄H₃₀N₇O₂ (M+H)⁺: m/z=568.2; found 568.3.

Step 6.3-(8-Amino-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(110 mg, 0.194 mmol) and TFA (746 μL, 9.69 mmol) was stirred at 80° C.for 30 min, cooled to room temperature, and concentrated. The resultingresidue was purified via prep-LCMS (pH 2) to give the product as a whitesolid (TFA salt) (57 mg, 90%). LC-MS calculated for C₁₈H₁₄N₇ (M+H)⁺:m/z=328.1; found 328.1.

Step 7.3-(8-Amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-amino-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(TFA salt) (35 mg, 0.079 mmol) in DMF (0.5 mL)/DCM (0.5 mL) was addedNBS (14.1 mg, 0.079 mmol). The reaction mixture was then stirred at roomtemperature for 1 h, and concentrated to afford the crude product, whichwas used in the next step without further purification. LC-MS calculatedfor C₁₈H₁₃BrN₇ (M+H)⁺: m/z=406.0; found 406.0.

Step 8.3-(8-Amino-2-(pyridin-2-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(15 mg, 0.037 mmol), 4-(tributylstannyl)pyrimidine (20 mg, 0.055 mmol),and copper(I) chloride (4.4 mg, 0.044 mmol), lithium chloride (1.9 mg,0.044 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.3 mg, 3.7μmol) in THF (1 mL) was purged with N₂, and stirred at 90° C. for 2 h.The reaction mixture was then cooled to room temperature, diluted withmethanol, and purified via prep-LCMS (pH 2, acetonitrile/water with TFA)to give the desired product as a TFA salt. LC-MS calculated forC₂₂H₁₆N₉(M+H)⁺: m/z=406.2; found 406.2.

Example 28.3-(8-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-Amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 27, Step 7; 10 mg, 0.025 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(10 mg, 0.042 mmol), cesium carbonate (37.6 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated and purified by preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₄H₁₉N₈O (M+H)⁺: 435.2; found 435.2.

Example 29.3-(8-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile”

A mixture of 6-chloro-2-methylpyridazin-3(2H)-one (30 mg, 0.21 mmol),bis(pinacolato)diboron (53 mg, 0.21 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(15.7 mg, 0.02 mmol) (XPhos Pd G2) and potassium acetate (61.7 mg, 0.63mmol) in 1,4-dioxane (1 mL) was stirred at 100° C. for 1 h.3-(8-Amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 27, Step 7; 10 mg, 0.025 mmol), cesium carbonate (37.6 mg,0.116 mmol) and water (0.2 mL) were then added to the reaction mixture.The resulting mixture was heated at 90° C. for 1 h. The mixture wasconcentrated and purified by preparative LCMS (pH 2, acetonitrile/waterwith TFA) to afford the desired product as TFA salt. LCMS calculated forC₂₃H₁₈N₉O (M+H)⁺: 436.2; found 436.2.

¹H NMR (500 MHz, DMSO) δ 8.66-8.62 (d, J=5.1 Hz, 1H), 8.09-8.02 (d,J=1.8 Hz, 1H), 7.88-7.85 (t, J=1.8 Hz, 1H), 7.85-7.81 (m, 3H), 7.78-7.72(d, J=9.6 Hz, 1H), 7.66-7.51 (m, 4H), 7.10-7.06 (d, J=9.6 Hz, 1H),4.59-4.48 (s, 2H), 3.53-3.43 (s, 3H).

Example 30.(S)-1-(2-((8-Amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)pyrrolidine-3-carboxylicAcid

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A microwave vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 27, Step 4; 0.15 g, 0.270 mmol), palladium acetate (1.1 mg, 4.7μmol), and2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine(4.1 mg, 9.5 μmol), the vial was then evacuated under high vacuum andbackfilled with nitrogen. THF (2.0 mL) was then added to the reactionvial. The mixture was cooled to 0° C. and the(2-chloro-6-fluorobenzyl)zinc(II) chloride (0.5 M THF solution, 1.08 mL)was added slowly via a syringe. The reaction mixture was then stirred at60° C. for 2 h, cooled to room temperature, and partitioned betweenethylacetate and saturated NH₄Cl solution. The layers were separated andthe aqueous layer was extracted with ethylacetate. The combined organiclayers were washed with water and brine, dried over MgSO₄, andconcentrated. The resulting residue was purified via flashchromatography to afford the product. LC-MS calculated for C₃₅H₂₉ClFN₆O₂(M+H)⁺: m/z=619.2; found 619.3.

Step 2:3-(8-Amino-5-bromo-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(100 mg, 0.161 mmol) and TFA (746 μL, 9.69 mmol) was stirred at 100° C.for 10 min, cooled to room temperature, and concentrated. The resultingresidue was dissolved in DMF, and a DMF (0.5 mL) solution ofN-bromosuccinimide (28 mg, 0.161 mmol) was added dropwise at 0° C. Theresulting mixture was stirred at 0° C. for 10 min. The reaction mixturewas diluted with sat. NaHCO₃. The mixture was extracted with DCM. Theorganic phase was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified with flash chromatography to givethe desired product as a light yellow oil. LC-MS calculated forC₁₉H₁₂BrClFN₆ (M+H)⁺: m/z=457.0; found 457.1.

Step 3:3-(8-Amino-2-(2-chloro-6-fluorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-5-bromo-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(51 mg, 0.11 mmol), CuI (4.2 mg, 0.021 mmol), CsF (33 mg, 0.22 mmol),tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.012 mmol), and4-(tributylstannyl)pyrimidine (49 mg, 0.13 mmol) in 1,4-dioxane (2 mL)was heated at 140° C. for 1 h in a microwave reactor. The reactionmixture was concentrated under vacuum and the resulting residue waspurified with flash chromatography to give the desired product as alight yellow oil. LC-MS calculated for C₂₃H₁₅ClFN₈ (M+H)⁺: m/z=457.1found 457.1.

Step 4:3-(8-Amino-2-(2-fluoro-6-vinylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-2-(2-chloro-6-fluorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(50 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (34mg, 0.22 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (8.5 mg, 10.8 μmol) and K₃PO₄ (47 mg, 0.22 mmol) in 1,4-dioxane (2mL)/water (0.4 mL) was stirred at 110° C. for 1 h. The reaction mixturewas concentrated under vacuum and the resulting residue was purifiedwith flash chromatography to give the desired product as a light yellowoil. LC-MS calculated for C₂₅H₁₈FN₈ (M+H)⁺: m/z=449.2; found 449.1.

Step 5:3-(8-Amino-2-(2-fluoro-6-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-amino-2-(2-fluoro-6-vinylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(40 mg, 0.089 mmol) in THF (1 mL) and water (1 mL) was added 0.157 Mosmium tetraoxide in water (0.02 mmol). After 2 min, sodiummetaperiodate (86 mg, 0.4 mmol) was added. The reaction mixture washeated at 60° C. for 1 h before quenched with sat. Na₂S₂O₃. The mixturewas extracted with DCM.

The organic phase was washed with brine, dried over Na₂SO₄, filtered,and concentrated to afford the product as a light yellow oil. LC-MScalculated for C₂₄H₁₆FN₈O (M+H)⁺: m/z=451.1; found 451.1.

Step 6:(S)-1-(2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)pyrrolidine-3-carboxylicAcid

To a solution of3-(8-amino-2-(2-fluoro-6-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.02 mmol) in DCM (0.5 mL) was added(S)-pyrrolidine-3-carboxylic acid (4.6 mg, 0.04 mmol) then acetic acid(4 μL, 0.08 mmol). After 1 h, sodium triacetoxyborohydride (8.5 mg, 0.04mmol) was added to the reaction. The reaction was stirred overnight andthe mixture was concentrated and purified by preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₉H₂₅FN₉O₂(M+H)⁺: 550.2 found 550.2.

Example 31.1-(2-((8-Amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)azetidine-3-carboxylicAcid

The title compound was prepared using similar procedures as describedfor Example 30, with azetidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid in Step 6. The reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₂₈H₂₃FN₉O₂(M+H)⁺: 536.2 found536.2.

Example 32 and Example 33.3-(2-((1H-Pyrrolo[2,3-b]pyridin-1-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrileand3-(2-((7H-pyrrolo[2,3-b]pyridin-7-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(362 mg, 0.66 mmol) (from Example 27, Step 4),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (204 mg, 1.32 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (51 mg, 64.8 μmol) and K₃PO₄ (282 mg, 1.32 mmol) in 1,4-dioxane (5mL)/water (1 mL) was stirred at 80° C. for 1 h. The reaction mixture wasconcentrated under vacuum and the resulting residue was purified withflash chromatography to give the desired product as a light yellow oil.LC-MS calculated for C₃₀H₂₇N₆O₂ (M+H)⁺: m/z=503.2; found 503.2.

Step 2:3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(241 mg, 0.48 mmol) in DCM (5 mL) was added NBS (84.6 mg, 0.48 mmol).The reaction mixture was then stirred at room temperature for 1 h, andconcentrated to afford the crude product, which was used in the nextstep without further purification. LC-MS calculated forC₃₀H₂₆BrN₆O₂(M+H)⁺: m/z=581.1; found 581.1.

Step 3:3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(203 mg, 0.35 mmol) in THF (4 mL) and water (4 mL) was added 0.157 Mosmium tetraoxide in water (0.1 mmol). After 2 min, sodium metaperiodate(430 mg, 2 mmol) was added. The reaction mixture was heated at 60° C.for 1 h before quenched with sat. Na₂S₂O₃. The mixture was extractedwith DCM. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude material was dissolved in DCM (1mL) and MeOH (3 mL), which was cooled to −78° C. before NaBH₄ (13 mg,0.35 mmol) was added. The resulting mixture was warmed to 0° C. andstirred at this temperature for 10 min. Water (10 mL) was then added andthe mixture was extracted with DCM. The organic phase was washed withbrine, dried over Na₂SO₄, filtered, and concentrated to afford theproduct as a light yellow oil. LC-MS calculated for C₂₉H₂₆BrN₆O₃(M+H)⁺:m/z=585.1; found 585.1.

Step 4:3-(8-(Bis(4-methoxybenzyl)amino)-2-(hydroxymethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(257 mg, 0.44 mmol), CuI (17 mg, 0.084 mmol), CsF (132 mg, 0.88 mmol),tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.048 mmol), and4-(tributylstannyl)pyrimidine (196 mg, 0.52 mmol) in 1,4-dioxane (4 mL)was heated at 140° C. for 1 h in a microwave reactor. The reactionmixture was concentrated under vacuum and the resulting residue waspurified with flash chromatography to give the desired product as alight yellow oil. LC-MS calculated for C₃₃H₂₉N₈O₃ (M+H)⁺: m/z=585.2found 585.2.

Step 5:3-(8-(Bis(4-methoxybenzyl)amino)-2-(bromomethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(Bis(4-methoxybenzyl)amino)-2-(hydroxymethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(234 mg, 0.4 mmol) was dissolved in THF (5 mL), and PBr₃ (0.077 mL, 0.8mmol) was added. The mixture was stirred at 60° C. for 4 h. Aftercompletion, the reaction was quenched by adding sat. NaHCO₃, the mixturewas then extracted with EtOAc. The organic phase was washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedwith flash chromatography to give the desired product as white solid.LC-MS calculated for C₃₃H28BrN₅O₂ (M+H)⁺: m/z=647.1; found 647.2.

Step 6:3-(2-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrileand3-(2-((7H-pyrrolo[2,3-b]pyridin-7-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(Bis(4-methoxybenzyl)amino)-2-(bromomethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(20 mg, 0.031 mmol) was dissolved in MeCN (2 mL), K₂CO₃ (8.6 mg, 0.062mmol) and 1H-pyrrolo[2,3-b]pyridine (7.3 mg, 0.062) were added. Themixture was stirred at 70° C. for 6 h. After completion, the solvent wasremoved under vacuum and 1 mL of TFA was added to the residue. Themixture was heated at 100° C. for 10 min. The reaction mixture wasconcentrated under vacuum and the resulting residue was dissolved inmethanol, and purified with prep-LCMS (pH 2, acetonitrile/water+TFA).The first peak was isolated as Example 32 as a TFA salt. LC-MScalculated for C₂₄H₁₇N₁₀ (M+H)⁺: m/z=445.2 found 445.1. The second peakwas isolated as Example 33, also as a TFA salt. LC-MS calculated forC₂₄H₁₇N₁₀ (M+H)⁺: m/z=445.2 found 445.1.

Example 34.3-(4-Amino-7-(4-(1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1: 4-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-2-methyloxazole

In a flame dried round-bottomed flask equipped with a magnetic stir bar,a solution of 1-(2-methyloxazol-4-yl)ethan-1-ol (1 g, 7.87 mmol) in DCM(10 mL) was treated at rt with tert-butylchlorodimethylsilane (1.3 g,7.88 mmol) followed by imidazole (0.54 g, 7.87 mmol) and the resultingsuspension was stirred for 1 h at rt. Water was added. The aq. layer wasextracted with DCM and the combined org. layers were dried over Na₂SO₄,filtered and the solvent was removed under reduced pressure. The residuewas purified with flash chromatography to give the desired product.LC-MS calculated for C₁₂H₂₄NO₂Si (M+H)⁺: m/z=242.2; found 242.2.

Step 2:4-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

In a flame dried round-bottomed flask equipped with a magnetic stir bar,was charged with (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (30 mg,0.045 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (190 mg, 1.5 mmol),and pentane (2.0 mL). The mixture was stirred at rt for 10 min. Then4,4′-di-tert-butyl-2,2′-dipyridyl (24 mg, 0.09 mmol) was added to thismixture and reaction stirred for additional 20 min.4-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyloxazole (300 mg, 1.24mmol) dissolved in Et₂O (2 mL) was added to the active catalyst mixture.The reaction was stirred at room temperature until completion. Solventwas removed under reduced pressure, and the crude material was purifiedwith flash chromatography to give the desired product. LC-MS calculatedfor the corresponding boronic acid C₁₂H₂₅BNO₄Si (M+H)⁺: m/z=286.2; found286.2.

Step 3:3-(4-Amino-7-(4-(1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 17, Step 1; 15 mg, 0.037 mmol),4-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole(29 mg, 0.08 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol) and Cs₂CO₃ (23.2 mg, 0.071 mmol) in1,4-dioxane (1 mL)/water (0.200 mL) was stirred at 90° C. for 1 h. Thereaction mixture was cooled down to room temperature before 6 N HCl (1mL) was added and resulting reaction mixture was stirred at 60° C. for30 min. The reaction was then diluted with methanol and purified withprep-LCMS (pH 2, acetonitrile/water+TFA) to give the desired product asa racemic material. Chiral separation was then conducted with chiralHPLC using AM-1 column and 30% EtOH in hexanes (20 ml/min) solventsystem. Peak 2 was collected as the desired product. LC-MS calculatedfor C₂₅H₂₂N₇O₂ (M+H)⁺: m/z=452.2; found 452.2.

Example 35.3-(4-Amino-7-(4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1: 2,2-Difluoro-1-(2-methyloxazol-4-yl)ethan-1-ol

To a solution of (bromodifluoromethyl)trimethylsilane (2.4 ml, 15.07mmol) in dry acetonitrile (10.1 ml) was added3-bromo-4-methylbenzaldehyde (2 g, 10.05 mmol) and triphenylphosphine(3.16 g, 12.06 mmol). The resulting suspension was cooled to 0° C. and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.4 ml, 20.10 mmol)[DMPU] was added dropwise. The cooling bath was removed and the reactionmixture was warmed to rt and stirred for 1 h. With the reaction flask ina rt water bath, aqueous 3 M KOH (1.7 g, 30.1 mmol) was added dropwisevia addition funnel. The bath was removed, and the reaction mixture wasstirred rapidly for 1.5 h. The reaction was then neutralized by aqueous2 M HCl (10.1 ml, 20.10 mmol), and the mixture was extracted with MTBE(2×75 ml). The combined organic layers were washed with Sat. NaClsolution, dried over Na₂SO₄, filtered, and concentrated to afford thecrude product as a brown oil, which was purified with flashchromatography to give the desired product. LC-MS calculated forC₆H₈F₂NO₂ (M+H)⁺: m/z=164.0; found 164.0.

Step 2:4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoroethyl)-2-methyloxazole

In a flame dried round-bottomed flask equipped with a magnetic stir bar,a solution of 2,2-difluoro-1-(2-methyloxazol-4-yl)ethan-1-ol (1.29 g,7.87 mmol) in DCM (10 mL) was treated at rt withtert-butylchlorodimethylsilane (1.3 g, 7.88 mmol) followed by imidazole(0.54 g, 7.87 mmol) and the resulting suspension was stirred for 1 h atrt. Water was added. The aq. layer was extracted with and the combinedorg. layers were dried over Na₂SO₄, filtered and the solvent was removedunder reduced pressure. The residue was purified with flashchromatography to give the desired product. LC-MS calculated forC₁₂H₂₂F₂NO₂Si (M+H)⁺: m/z=278.1; found 278.1.

Step 3:4-(1-((tert-Butyldimethylsilyl)oxy)-2,2-difluoroethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

In a flame dried round-bottomed flask equipped with a magnetic stir bar,was charged with (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (60 mg,0.09 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (834 mg, 3.0 mmol),and pentane (4.0 mL). The mixture was stirred at room temperature for 10min. Then 4,4′-di-tert-butyl-2,2′-dipyridyl (48 mg, 0.18 mmol) was addedto this mixture and reaction stirred for additional 20 min.4-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyloxazole (600 mg, 2.4mmol) dissolved in Et₂O (4 mL) was added to the active catalyst mixture.The reaction was stirred at room temperature until completion. Solventwas removed under reduced pressure, and the crude material was purifiedwith flash chromatography to give the desired product. LC-MS calculatedfor the corresponding boronic acid C₁₂H₂₂BF₂NO₄Si (M+H)⁺: m/z=322.2;found 322.1.

Step 4:3-(4-Amino-7-(4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 17, Step 1; 15 mg, 0.037 mmol),4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoroethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole(32 mg, 0.08 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.86 mg, 3.63 μmol) and Cs₂CO₃ (23.2 mg, 0.071 mmol) in1,4-dioxane (1 mL)/water (0.200 mL) was stirred at 90° C. for 1 h. Thereaction mixture was cooled down to room temperature before 6 N HCl (1mL) was added and resulting reaction mixture was stirred at 60° C. for30 min. The reaction was then diluted with methanol and purified withprep-LCMS (pH 2, acetonitrile/water+TFA) to give the desired product asa racemic material. Chiral separation was then conducted with chiralHPLC using Phenomenex LUX Amylose-1 column and 45% EtOH in hexanes (20ml/min) solvent system. Peak 1 was collected as the desired product.LC-MS calculated for C₂₅H₂₀F₂N₇O₂ (M+H)⁺: m/z=488.2; found 488.2.

Example 36.3-(4-Amino-7-(1-ethyl-1H-1,2,3-triazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1: 1-Ethyl-5-(trimethylstannyl)-1H-1,2,3-triazole

To a stirred solution of 1-ethyl-1H-1,2,3-triazole (0.58 g, 6.0 mmol) inanhydrous tetrahydrofuran (50 mL) at −78° C. under an atmosphere ofnitrogen was added n-butyllithium (2.5M solution in hexanes, 2.6 mL, 6.6mmol) dropwise over ten minutes. On complete addition the reaction wasallowed to warm to −30 OC and stirred for 2 h. A solution ofchlorotrimethylstannane (1.3 g, 6.6 mmol) in tetrahydrofuran (2 mL) wasadded dropwise over 10 minutes then the reaction mixture was allowed towarm to room temperature over 2 h. The reaction was quenched by theaddition of saturated ammonium chloride solution (5 mL) then dilutedwith water (20 mL). The solvent was evaporated in vacuo and the aqueousphase extracted with ethyl acetate (2×30 mL). The combined organic layerwas dried over sodium sulfate, filtered and concentrated to afford thedesired product as a pale oil. LC-MS calculated for C₇H₁₆N₃Sn (M+H)⁺:m/z=262.0; found 262.0.

Step 2:3-(4-Amino-7-(1-ethyl-1H-1,2,3-triazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 17, Step 1; 15 mg, 0.037 mmol), CuI (17 mg, 0.084 mmol), CsF(132 mg, 0.88 mmol), tetrakis(triphenylphosphine)palladium(0) (48 mg,0.048 mmol), and 1-ethyl-5-(trimethylstannyl)-1H-1,2,3-triazole (135 mg,0.52 mmol) in 1,4-dioxane (4 mL) was heated at 140° C. for 1 h in amicrowave reactor. The reaction mixture was concentrated under vacuumand the resulting residue was dissolved in methanol, and purified withpreparative LCMS (pH 2, acetonitrile/water with TFA) to afford thedesired product as TFA salt. LCMS calculated for C₂₃H₂₀N₉(M+H)⁺:m/z=422.2 found 422.2.

Example 37.3-(4-Amino-7-(1-methyl-1H-1,2,3-triazol-5-yl)-2-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 36, with 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazolereplacing 1-ethyl-5-(trimethylstannyl)-1H-1,2,3-triazole in Step 2. Thereaction mixture was purified with preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₂H₁₈N₉(M+H)⁺: m/z=408.2 found 408.1.

Example 38.3-(4-Amino-2-((2-fluorophenyl)(hydroxy)methyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound, an enatiomeric pure compound, was prepared byseparating a racemic mixture of Example 23. The chiral separation wasconducted with chiral HPLC using Phenomenex Lux Cellulose-4, 21.2×250mm, 5 um column and 40% EtOH in hexanes (20 ml/min) solvent system. Peak1 was collected as the title compound. LC-MS calculated for C₂₄H₁₇FN₇O(M+H)⁺: m/z=438.2 found 438.2.

Example 39.3-(8-Amino-2-(2-fluorophenoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-2-(3-fluorophenoxy)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A reaction vial was charged with3-(8-(bis(4-methoxybenzyl)amino-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(25 mg, 0.045 mmol) (from Example 27, Step 4), 3-fluorophenol (7.6 mg,0.068 mmol), dimethylglycine (4.2 mg, 0.041 mmol), CuI (2.6 mg, 0.014mmol), cesium carbonate (29 mg, 0.090 mmol) and dioxane (1 mL). Thereaction mixture was purged with nitrogen for 5 min before heating to100° C. and stirring for 15 h. The reaction mixture was then dilutedwith water and ethyl acetate. The organic layer was separated, washedwith brine, dried over Na₂SO₄, filtered and concentrated. The resultingresidue was purified via flash chromatography to give the desiredproduct as a white solid (18 mg, 56%). LC-MS calculated for C₃₄H₂₈FN₆O₃(M+H)⁺: m/z=587.2; found 587.2.

Step 2:3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-fluorophenoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(Bis(4-methoxybenzyl)amino)-2-(3-fluorophenoxy)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(18 mg, 0.025 mmol) was dissolved dichloromethane (1 mL), and NBS (8 mg,0.045 mmol) was added. The mixture was stirred at rt for 0.5 h beforequenching by the addition of aqueous Na₂SO₃ solution. The organic layerwas separated, dried over Na₂SO₄, filtered and concentrated. The crudebrominated product was added LiCl (1.3 mg, 0.030 mmol), CuI (5.8 mg,0.030 mmol), Pd₂(dba)₃ (2.3 mg, 0.003 mmol), PPh₃ (1.3 mg, 0.005 mmol)and 4-(tributylstannyl)pyrimidine (14 mg, 0.038 mmol). The reactionmixture was dissolved in dioxane, and purged with nitrogen for 5 min,before heating to 100° C. for 15 h. The reaction mixture was then cooledto rt, filtered, concentrated, and purified via flash chromatography togive the desired product as a white solid (10 mg, 60%). LC-MS calculatedfor C₃₈H₃₀FN₈O₃(M+H)⁺: m/z=665.2; found 665.2.

Step 3:3-(8-Amino-2-(2-fluorophenoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-fluorophenoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.015 mmol) was added TFA (0.5 mL), and stirred at 100° C. for 5min. The reaction mixture was then cooled to room temperature, solventremoved, diluted with methanol, and purified via prep-LCMS (pH 2,acetonitrile/water with TFA) to give the desired product as a TFA salt.LC-MS calculated for C₂₂H₁₄FN₈O (M+H)⁺: m/z=425.1; found 425.2.

Example 40.3-(8-Amino-2-(hydroxy(pyridin-2-yl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(1.00 g, 1.99 mmol) (From Example 32, Step 1) and sodium periodate (1.92g, 8.95 mmol) in THF (10 mL) and water (10 mL) was added osmiumtetroxide (4% solution in water, 1.21 mL, 0.20 mmol). The reactionmixture was stirred at 60° C. for 1 h. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The resulting residue waspurified using flash chromatography to give the desired product (0.74 g,74%). LC-MS calculated for C₂₉H₂₅N₆O₃ (M+H)⁺: m/z=505.2; found 505.2.

Step 2:3-(8-(Bis(4-methoxybenzyl)amino)-2-(hydroxy(pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of 2-iodopyridine (0.40 g, 1.95 mmol) in THF (2 mL) wasadded isopropylmagnesium chloride lithium chloride complex solution (1.3M, 1.3 mL, 1.71 mmol) dropwise at 0° C. The reaction mixture was stirredat 0° C. for 30 minutes. A solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.25 g, 0.49 mmol) in THF (2 mL) was added dropwise and the reactionmixture was stirred at 0° C. for 1 h. The reaction mixture was thenquenched with saturated aqueous NH₄Cl solution and diluted with DCM. Thelayers were separated, the aqueous layer was extracted with DCM, and thecombined organic fractions were dried over MgSO₄, filtered andconcentrated. The resulting residue was purified using flashchromatography to give the desired product (0.19 g, 67%). LC-MScalculated for C₃₄H₃₀N₇O₃ (M+H)⁺: m/z=584.2; found 584.3.

Step 3:3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(hydroxy(pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(hydroxy(pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.17 g, 0.29 mmol) in DCM (3 mL) was added a solution of NBS (0.052 g,0.29 mmol) in DCM (3 mL) dropwise at 0° C. The reaction mixture wasstirred at 0° C. for 1 h. The reaction mixture was concentrated, and theresulting residue was purified using flash chromatography to give thedesired product (0.15 g, 78%). LC-MS calculated for C₃₄H₂₉BrN₇O₃ (M+H)⁺:m/z=662.2; found 662.2.

Step 4:3-(8-Amino-2-(hydroxy(pyridin-2-yl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(hydroxy(pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.010 g, 0.015 mmol),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (0.013g, 0.060 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.004 g, 0.005 mmol) in dioxane (0.250 mL) and water (0.050 mL)was added potassium phosphate tribasic (0.016 g, 0.075 mmol). Thereaction mixture was stirred at 100° C. for 1 h. The reaction mixturewas then diluted with water and DCM. The layers were separated, theaqueous layer was extracted with DCM, and the combined organic fractionswere dried over MgSO₄, filtered and concentrated. The crude material wasdissolved in TFA (1 mL) and heated to 80° C. for 20 minutes. Thesolution was diluted with DMF (4 mL) and purified with prep-LCMS (pH=2,acetonitrile/water+TFA) to give the desired product as a pair ofenantiomers, and as a TFA salt (3.5 mg, 43%). LC-MS calculated forC₂₂H₁₇N₅O₂ (M+H)⁺: m/z=425.2; found 425.3.

Example 41.3-(8-Amino-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A microwave vial was charge with3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(350 mg, 0.630 mmol) (from example 27 step 4), palladium acetate (7.07mg, 0.032 mmol), and2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine(27.5 mg, 0.063 mmol) was evacuated under high vacuum and backfilledwith nitrogen. (2-chlorobenzyl)zinc(II) chloride (1386 μl, 0.693 mmol)was added via syringe. After addition, the reaction was heated to 60° C.for 1 h. The reaction solution was partitioned between EtOAc and sat.NH₄Cl solution. The layers were separated and the aqueous extractedfurther with EtOAc (2×). The combined organics were washed with waterand brine, dried over MgSO₄, and concentrated. The residue was purifiedwith flash chromatography to give the desired product (0.32 g, 82%).LC-MS calculated for C₃₅H₃₀ClN₆O₂(M+H)⁺: m/z=601.2; found 601.2.

Step 2.3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.379 g, 0.631 mmol) in DCM (6.3 ml) was added1-bromopyrrolidine-2,5-dione (0.107 g, 0.599 mmol) at 0° C. Afterstirring at room temperature for 1 h, the reaction mixture was dilutedwith water. The organic layer was separated, dried over Na₂SO₄, filteredand concentrated. The residue was purified with silica gel column togive the desired product (0.38 g, 89%). LC-MS calculated forC₃₅H₂₉BrClN₆O₂(M+H)⁺: m/z=679.1, 681.1; found 679.2, 681.2.

Step 3.3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(381 mg, 0.560 mmol), 4-(tributylstannyl)pyrimidine (310 mg, 0.840mmol), and copper(I) chloride (66.6 mg, 0.672 mmol), lithium chloride(28.5 mg, 0.672 mmol) and tetrakis(triphenylphosphine)palladium(0) (64.7mg, 0.056 mmol) in THF (6 ml) was first purged with N₂, and then heatedand stirred at 90° C. for 2 h. The reaction mixture was diluted withethyl acetate and water. The reaction mixture was filtered through a padof Celite®. The organic layer was separated and dried over Na₂SO₄,filtered and concentrated. The residue was purified with flashchromatography to give the desired product (0.31 g, 83%). LC-MScalculated for C₃₉H₃₂ClN₈O₂(M+H)⁺: m/z=679.2; found 679.2.

Step 4.3-(8-Amino-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.015 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.68 mg, 0.018 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.158 mg, 1.472 μmol) and tripotassium phosphate hydrate (7.46mg, 0.032 mmol) in 1,4-dioxane (1.0 mL)/water (0.3 mL) was stirred at80° C. for 1 h. The reaction mixture was diluted with EtOAc and water,the organic layer was separated and concentrated. The residue wastreated with TFA (1 mL) at 80° C. for 20 min. The solvent was removed,the residue was dissolved in methanol and DMSO, then purified withprep-LCMS (pH 2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₇H₂₁N₁₀ (M+H)⁺: m/z=485.2; found 485.2.

Example 42.3-(8-Amino-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.697 g, 1.228 mmol) (From Example 27, Step 5) in DCM (12 ml) was added1-bromopyrrolidine-2,5-dione (0.219 g, 1.228 mmol) at 0° C. Afterstirring at room temperature for 1 h, the reaction mixture was dilutedwith water. The organic layer was separated, dried over Na₂SO₄, filteredand concentrated. The residue was purified with silica gel column togive the desired product (0.74 g, 93%). LC-MS calculated forC₃₄H₂₉BrN₇O₂(M+H)⁺: m/z=646.2, 648.2; found 646.2, 648.2.

Step 2.3-(8-(Bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-5-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(390 mg, 0.603 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(111 mg, 0.724 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (47.5 mg, 0.060 mmol) and tripotassium phosphate hydrate (306 mg,1.327 mmol) in 1,4-dioxane (5.0 mL)/water (1.7 mL) was stirred at 80° C.for 1 h. The reaction mixture was diluted with EtOAc and water. Theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated. The residue was purified with silica gel column to givethe desired product (0.28 g, 77%). LC-MS calculated for C₃₆H₃₂N₇O₂(M+H)⁺: m/z=594.3; found 594.3.

Step 3.3-(8-(Bis(4-methoxybenzyl)amino)-5-formyl-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-5-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(277 mg, 0.467 mmol) in THF (2.3 mL) and water (2.3 mL) was added 4%osmium tetraoxide in water (233 μl, 0.037 mmol) and sodium metaperiodate(449 mg, 2.1 mmol). The reaction mixture was stirred at 60° C. for 1 h.The mixture was filtered through a plug of Celite®, rinsed with THF. Theorganic layer was concentrated under vacuum. The residue was purifiedwith flash chromatography to give the desired product (0.21 g, 76%).LC-MS calculated for C₃₅H₃₀N₇O₃ (M+H)⁺: m/z=596.2; found 596.2.

Step 4.3-(8-Amino-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(38 mg, 0.064 mmol) in methanol (0.3 mL) and 1,2-dichloroethane (0.3 mL)was added 1-((1-isocyanoethyl)sulfonyl)-4-methylbenzene (13.35 mg, 0.064mmol). The resulting mixture was heated at 70° C. overnight. Thereaction mixture was diluted with DCM and water, the organic layer wasseparated and concentrated. The residue was treated with TFA (1 mL) at80° C. for 20 min. The solvent was removed, the residue was dissolved inmethanol and DMSO, then purified with prep-LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₂H₁₇N₈O (M+H)⁺: m/z=409.2; found 409.1.

Example 43.3-(8-Amino-5-(4-ethyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 42 with 1-((1-isocyanopropyl)sulfonyl)-4-methylbenzenereplacing 1-((1-isocyanoethyl)sulfonyl)-4-methylbenzene in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₃H₁₉N₈O (M+H)⁺: m/z=423.2; found 423.2.

Example 44.3-(8-Amino-5-(3-methylpyridin-4-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 27, Step 7; 10 mg, 0.025 mmol), (3-methylpyridin-4-yl)boronicacid (4.1 mg, 0.030 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.9 mg, 2.5 μmol) and tripotassium phosphate hydrate (12.5 mg,0.054 mmol) in 1,4-dioxane (1.0 mL)/water (0.3 mL) was stirred at 80° C.for 1 h. The reaction mixture was diluted with DCM and water, theorganic layer was separated and concentrated. The resulting residue wasdissolved in methanol and DMSO, then purified with prep-LCMS (pH 2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₄H₁₉N₈(M+H)⁺: m/z=419.2; found 419.2.

Example 45.3-(8-Amino-2-(imidazo[1,2-a]pyridin-8-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A microwave vial charged with3-(8-(bis(4-methoxybenzyl)amino)-2-(bromomethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(20 mg, 0.031 mmol) (from Example 32, Step 5),8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(15.08 mg, 0.062 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.430 mg, 3.09 μmol) and cesium carbonate (30.2 mg, 0.093 mmol)was sealed and evacuated under high vacuum and refilled with nitrogen(repeated three times). 1,4-Dioxane (2.0 mL) and water (0.67 mL) wasstirred at 90° C. overnight. The reaction mixture was diluted with ethylacetate and water. The organic layer was separated and concentrated. Theresidue was treated with TFA (1 mL) at 80° C. for 20 min. After removalof the volatile, the residue was dissolved in methanol and DMSO andpurified with prep-LCMS (pH 2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₂₄H₁₇N₁₀ (M+H)⁺:m/z=445.2; found 445.2.

Example 46.3-(8-Amino-2-(pyrazolo[1,5-a]pyridin-7-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 45 with7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridinereplacing8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₄H₁₇N₁₀ (M+H)⁺: m/z=445.2; found 445.2.

Example 47 and Example 48.3-(2-((2H-Indazol-2-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrileand3-(2-((1H-Indazol-1-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(bromomethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(15 mg, 0.023 mmol) (from Example 32, Step 5), 1H-indazole (4.1 mg,0.035 mmol), cesium carbonate (22.64 mg, 0.069 mmol) in DMF (300 μl) wasstirred at 50° C. for 15 min. The reaction was diluted with EtOAc andwater. The organic layer was separated and concentrated. The residue wastreated with TFA (1 mL) at 80° C. for 20 min. The volatile was removedin vacuo, the residue was dissolved in methanol and DMSO and purifiedwith prep-HPLC (pH=2, acetonitrile/water+TFA) to give the two productsboth as TFA salts. LC-MS calculated for both compounds C₂₄H₁₇N₁₀ (M+H)⁺:m/z=445.2; found 445.2.

Example 49.3-(8-Amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

Step 1: Methyl3-bromo-1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-1,2,4-triazole-5-carboxylate

To a solution of methyl 3-bromo-1H-1,2,4-triazole-5-carboxylate (5.0 g,24.3 mmol), 3-(2-bromoacetyl)benzonitrile (5.44 g, 24.3 mmol) in DMF(100 mL) was added potassium carbonate (3.35 g, 24.3 mmol). The reactionmixture was stirred at ambient temperature for 2 h. The reaction mixturewas then diluted with water and DCM. The organic layer was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresulting residue was purified via flash chromatography to give thedesired product as a white solid (5.2 g, 61%). LC-MS calculated forC13H10BrN₄O₃ (M+H)⁺: m/z=349.0; found 349.0.

Step 2:3-(2-Bromo-8-oxo-7,8-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Methyl3-bromo-1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-1,2,4-triazole-5-carboxylate(10.5 g, 30.1 mmol) was dissolved in acetic acid (100 mL), and ammoniumacetate (23.18 g, 301 mmol) was added. The mixture was stirred at 110°C. for 12 h. After cooling to room temperature, the reaction mixture wasdiluted with water. The resulting precipitate was collected viafiltration, washed with water, and dried under vacuum to afford theproduct (8.4 g, 88%). LC-MS calculated for C₁₂H7BrN₅O (M+H)⁺: m/z=316.0;found 316.0.

Step 3:3-(2-Bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-bromo-8-oxo-7,8-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(8.4 g, 26.6 mmol) and POCl₃ (49.5 mL, 531 mmol) was stirred at 110° C.overnight. After cooling to room temperature, the reaction mixture wasslowly added to a flask containing ice and sodium bicarbonate. Theresulting precipitate was collected via filtration, washed with water,and dried to afford the product (8.8 g, 99%). LC-MS calculated forC₁₂H₆BrClN₅ (M+H)⁺: m/z=336.0; found 336.0.

Step 4:3-(8-(Bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(8.99 g, 26.9 mmol), bis(4-methoxybenzyl)amine (10.37 g, 40.3 mmol), andDIPEA (9.4 mL, 53.7 mmol) in DMF (134 mL) was stirred at 65° C.overnight. The reaction mixture was cooled to room temperature, anddiluted with water. The resulting precipitate was collected viafiltration, and dried to afford the product (14.1 g, 94%). LC-MScalculated for C₂₈H₂₄BrN₆O₂(M+H)⁺: m/z=555.1; found 555.1.

Step 5:3-(8-(Bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10.0 g, 18.0 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(3.88 g, 25.2 mmol), potassium phosphate tribasic (9.55 g, 45.0 mmol)andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(567 mg, 0.72 mmol) in 1,4-dioxane (200 mL) and water (50 mL) wasstirred at 85° C. for 2 hrs. The reaction mixture was cooled to roomtemperature, and most of 1,4-dioxane was removed. The resultingprecipitate was collected via filtration, washed with water and dried toafford the crude product (9.1 g), which was used in the next stepdirectly. LC-MS calculated for C₃₀H₂₇N₆O₂ (M+H)⁺: m/z=503.2; found503.1.

Step 6.3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(717 mg, 1.43 mmol) in 10 mL of dichloromethane,1-bromopyrrolidine-2,5-dione (254 mg, 1.43 mmol) was added at 0° C. Theresulting mixture was stirred for 4 hrs, and directly purified by asilica gel column to afford the desired product (780 mg, 94%). LC-MScalculated for C₃₀H₂₆BrN₆O₂(M+H)⁺: m/z=581.1; found 581.2.

Step 7:3-(8-(Bis(4-methoxybenzyl)amino)-5-(pyrimidin-4-yl)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(260 mg, 0.45 mmol), 4-(tributylstannyl)pyrimidine (215 mg, 0.58 mmol),lithium chloride (28.4 mg, 0.67 mmol), copper(I) chloride (67 mg, 0.67mmol), and Tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol)in THF (5 mL) was stirred at 90° C. for 45 mins. The reaction mixturewas quenched with water and extracted with dichloromethane. The combinedorganic layers were concentrated, and purified by a silica gel column toafford the desired product (176 mg, 67%). LC-MS calculated forC₃₄H₂₉N₈O₂ (M+H)⁺: m/z=581.2; found 581.1.

Step 8:3-(8-(Bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-(pyrimidin-4-yl)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(176 mg, 0.3 mmol), osmium(VIII) oxide (3 mg in 0.3 mL water, 0.015mmol), and sodium periodate (292 mg, 1.36 mmol) in THF/water (1:1, 6 mL)was stirred at 65° C. for 1 h. The reaction mixture was cooled to roomtemperature, and extracted with dichloromethane. The combined organiclayers were concentrated, and purified by silica gel column to affordthe desired product (130 mg, 74%). LC-MS calculated for C₃₃H₂₇N₈O₃(M+H)⁺: m/z=583.2; found 583.2.

Step 9: 3-(8-Amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Preparation of the Grignard reagent: To a solution of1,3-difluoro-2-iodobenzene (142 mg, 0.6 mmol) in tetrahydrofuran (1 mL),isopropylmagnesium chloride solution (296 μl, 2 M) was added at −10° C.The resulting mixture was stirred for 1 h, and used directly in thefollowing step.

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(120 mg, 0.2 mmol) in THF (2 mL), the freshly prepared Grignard reagentfrom previous step was added at −10° C. The reaction mixture was stirredfor 30 min, quenched with ammonium chloride solution (4 mL), andextracted with dichloromethane. The combined organic layers wereconcentrated under vacuum. The resulting material was dissolved in TFA(5 mL), and stirred at 80° C. for 20 min. The reaction mixture was thencooled to room temperature, concentrated, and basified by adding aqueousNaHCO₃ solution. The crude material was directly purified by a silicagel column to afford the desired product (60 mg, 64%) as a racemicmixture. The product was then separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 75% EtOH inhexanes (20 mL/min) solvent system. Peak 1 was isolated, and furtherpurified via preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired product as a TFA salt. LC-MS calculated for C₂₃H₁₅F₂N₈O(M+H)⁺: m/z=457.1; found 457.0.

Example 50.3-(8-Amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 49. The product was separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 75% EtOH inhexanes (20 mL/min) solvent system. Peak 2 was isolated, and furtherpurified via preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired product as a TFA salt. LC-MS calculated for C₂₃H₁₅F₂N₈O(M+H)⁺: m/z=457.1; found 457.0.

¹H NMR (600 MHz, DMSO-d₆) δ 9.14 (d, J=1.3 Hz, 1H), 8.95 (d, J=5.2 Hz,1H), 7.90 (dd, J=5.2, 1.4 Hz, 1H), 7.88 (s, 1H), 7.78 (dt, J=7.6, 1.4Hz, 1H), 7.74 (t, J=1.4 Hz, 1H), 7.54 (dt, J=7.9, 1.3 Hz, 1H), 7.51-7.40(m, 2H), 7.09 (t, J=8.4 Hz, 2H), 6.27 (s, 1H).

Example 51.3-(8-Amino-2-((2,5-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(115 mg, 0.2 mmol) in THF (1 mL), the freshly prepared Grignard reagent(prepared using a similar procedure as described in Example 49, Step 9,using 1,4-difluoro-2-iodobenzene instead of 1,3-difluoro-2-iodobenzene)was added at −10° C. The reaction mixture was stirred for 30 min,quenched with ammonium chloride solution (4 mL), and extracted withdichloromethane. The combined organic layers were concentrated undervacuum. The resulting material was dissolved in TFA (5 mL), and stirredat 80° C. for 20 min. The reaction mixture was then cooled to roomtemperature, concentrated, and basified by adding aqueous NaHCO₃solution. The crude material was directly purified by a silica gelcolumn to afford the desired product (70 mg, 77%) as a racemic mixture.The product was then separated with chiral HPLC using a chiral column(Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 40% EtOH in hexanes(20 mL/min) as the mobile phase. Peak 1 was isolated, and furtherpurified via preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired product as a TFA salt. LC-MS calculated for C₂₃H₁₅F₂N₈O(M+H)⁺: m/z=457.1; found 457.0.

Example 52.3-(8-Amino-2-((2,5-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 51. The product was separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 40% EtOH inhexanes (20 mL/min) as the mobile phase. Peak 2 was isolated, andfurther purified via preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₃H₁₅F₂N₈O (M+H)⁺: m/z=457.1; found 457.0.

Example 53.3-(8-Amino-2-((2,3-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of 1,2-difluoro-3-iodobenzene (70 mg, 0.3 mmol) intetrahydrofuran (1 mL), isopropylmagnesium chloride (150 μl, 2 Msolution) was added at −10° C., and the resulting mixture was stirredfor 1 h before a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(60 mg, 0.1 mmol) in THF (1 mL) was added at −10° C. The reactionmixture was stirred for 30 min, quenched with ammonium chloride solution(4 mL), and extracted with dichloromethane. The combined organic layerswere concentrated under vacuum. The resulting material was dissolved inTFA (5 mL), and stirred at 80° C. for 20 min. The reaction mixture wasthen cooled to room temperature, concentrated, and basified by addingaqueous NaHCO₃ solution. The crude material was directly purified by asilica gel column to afford the desired product (30 mg, 70%) as aracemic mixture. The resulting product was then separated with chiralHPLC using a chiral column (Phenomenex Lux 5 um Cellulose-4, 21.2×250mm) and 40% EtOH in hexanes (20 mL/min) as the mobile phase. Peak 1 wasisolated, and further purified via preparative LC/MS (pH=2,acetonitrile/water with TFA) to give the desired product as a TFA salt.LC-MS calculated for C₂₃H₁₅F₂N₈O (M+H)⁺: m/z=457.1; found 457.0.

Example 54.3-(8-Amino-2-((2,3-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 53. The product was separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 40% EtOH inhexanes (20 mL/min) as the mobile phase. Peak 2 was isolated, andfurther purified via preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₃H₁₅F₂N₈O (M+H)⁺: m/z=457.1; found 457.0.

Example 55.3-(8-Amino-2-((2-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(100 mg, 0.17 mmol) in THF (2 mL), the corresponding Grignard reagent(freshly prepared using a similar procedure as described in Example 49,Step 9, using 1-fluoro-2-iodobenzene instead of1,3-difluoro-2-iodobenzene) was added at −10° C. The reaction mixturewas stirred for 30 min, quenched with ammonium chloride solution (4 mL),and extracted with dichloromethane. The combined organic layers wereconcentrated under vacuum. The resulting material was dissolved in TFA(5 mL), and stirred at 80° C. for 20 min. The reaction mixture was thencooled to room temperature, concentrated, and basified by adding aqueousNaHCO₃ solution. The crude material was directly purified by a silicagel column to afford the desired product (60 mg, 50%) as a racemicmixture. The resulting product was then separated with chiral HPLC usinga chiral column (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 60%EtOH in hexanes (20 mL/min) as the mobile phase. Peak 1 was isolated,and further purified via preparative LC/MS (pH=2, acetonitrile/waterwith TFA) to give the desired product as a TFA salt. LC-MS calculatedfor C₂₃H₁₆FN₈O (M+H)⁺: m/z=439.1; found 439.0.

Example 56.3-(8-Amino-2-((2-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 55. The product was separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 60% EtOH inhexanes (20 mL/min) as the mobile phase. Peak 2 was isolated, andfurther purified via preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₃H₁₆FN₈O (M+H)⁺: m/z=439.1; found 439.0.

Example 57.3-(8-Amino-2-((2-chlorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(100 mg, 0.17 mmol) in THF (2 mL), the corresponding Grignard reagent(freshly prepared using a similar procedure as described in Example 49,Step 9, using 1-chloro-2-iodobenzene instead of1,3-difluoro-2-iodobenzene) was added at −10° C. The reaction mixturewas stirred for 30 min, quenched with ammonium chloride solution (4 mL),and extracted with dichloromethane. The combined organic layers wereconcentrated under vacuum. The resulting material was dissolved in TFA(5 mL), and stirred at 80° C. for 20 min. The reaction mixture was thencooled to room temperature, concentrated, and basified by adding aqueousNaHCO₃ solution. The crude material was directly purified by a silicagel column to afford the desired product (50 mg, 64%) as a racemicmixture. The resulting product was then separated with chiral HPLC usinga chiral column (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 45%EtOH in hexanes (20 mL/min) as the mobile phase. Peak 1 was isolated,and further purified via preparative LC/MS (pH=2, acetonitrile/waterwith TFA) to give the desired product as a TFA salt. LC-MS calculatedfor C₂₃H₁₆ClN₈O (M+H)⁺: m/z=455.1; found 455.1.

Example 58.3-(8-Amino-2-((2-chlorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 57. The product was separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.2×250 mm) and 45% EtOH inhexanes (20 mL/min) as the mobile phase. Peak 2 was isolated, andfurther purified via preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₃H₁₆ClN₈O (M+H)⁺: m/z=455.1; found 455.1.

Example 59.3-(8-Amino-2-(hydroxy(phenyl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(20 mg, 0.17 mmol) in THF (2 mL), phenylmagnesium chloride (3 M solutionin ethyl ether, 0.17 mL) was added at −10° C. The reaction mixture wasstirred for 30 min, quenched with ammonium chloride solution (4 mL), andextracted with dichloromethane. The combined organic layers wereconcentrated under vacuum. The resulting material was dissolved in TFA(5 mL), and stirred at 80° C. for 20 min. The reaction mixture was thencooled to room temperature, concentrated, and purified with preparativeLC/MS (pH=2, acetonitrile/water with TFA) to give the product as a TFAsalt. LC-MS calculated for C₂₃H₁₇N₈O (M+H)⁺: m/z=421.2; found 421.1.

Example 60.3-(8-Amino-2-(phenylsulfonyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-Amino-2-(phenylsulfonyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(33 mg, 0.06 mmol) (from Example 27, Step 4) and sodium benzenesulfinate(100 mg, 0.6 mmol) in 1 mL DMSO was stirred at 110° C. for 48 hrs, thereaction was quenched with ammonium chloride and extracted withdichloromethane. The combined organic layers were concentrated andpurified with silica gel column to afford the desired Product (18 mg,50%), LC-MS calculated for C₃₄H₂₉N₆O₄S (M+H)⁺: m/z=617.2; found 617.2.

Step 2:3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(phenylsulfonyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-Amino-2-(phenylsulfonyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(20 mg, 0.032 mmol) in 1 mL dichloromethane,1-bromopyrrolidine-2,5-dione (6 mg, 0.032 mmol) was added at 0° C. Theresulting mixture was stirred for 16 hrs before being purified by silicagel column to afford the desired product (18 mg, 80%). LC-MS calculatedfor C₃₄H₂₈BrN₆O₄S (M+H)⁺: m/z=695.1; found 695.2.

Step 3:3-(8-Amino-2-(phenylsulfonyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(phenylsulfonyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.014 mmol), 4-(tributylstannyl)pyrimidine (11 mg, 0.029 mmol),lithium chloride (1.0 mg, 0.022 mmol), copper(I) chloride (2.1 mg, 0.022mmol), and tetrakis(triphenylphosphine)palladium(0) (3.3 mg, 2.88 umol)in THF (2 mL) was stirred at 90° C. for 45 mins. The reaction mixturewas filtered and the organic solvent was removed by vacuo, the crudeproduct was dissolved in 3 mL TFA and stirred at 80° C. for 20 mins.After TFA being removed, the crude product was purified by preparativeLC/MS (pH=2, acetonitrile/water with TFA) to afford the desired productas a TFA salt. LC-MS calculated for C₂₂H₁₅N₅O₂S (M+H)⁺: m/z=455.1; found455.1.

Example 61.3-(8-Amino-2-(azetidine-1-carbonyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(2-(Azetidine-1-carbonyl)-8-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(99 mg, 0.18 mmol) and azetidine (50 mg, 0.89 mmol), PdCl₂(dppf) (26 mg,0.036 mmol) and Na₂CO₃ (57 mg, 0.48 mmol) in 5 mL 1,4-dioxane and 1 mLwater was stirred at 80° C. for 18 hrs under CO balloon atmosphere, thereaction was quenched with ammonium chloride and extracted withdichloromethane. The combined organic layers were concentrated andpurified with silica gel column to afford the desired Product (44 mg,44%), LC-MS calculated for C₃₂H₃₀N₇O₃ (M+H)⁺: m/z=560.2; found 560.2.

Step 2:3-(2-(Azetidine-1-carbonyl)-8-(bis(4-methoxybenzyl)amino)-5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(2-(azetidine-1-carbonyl)-8-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(40 mg, 0.125 mmol) in 3 mL dichloromethane,1-bromopyrrolidine-2,5-dione (23 mg, 0.125 mmol) was added at 0° C. Theresulting mixture was stirred for 16 hrs before being purified by silicagel column to afford the desired product (50 mg, 100%). LC-MS calculatedfor C₃₂H₂₉BrN₇O₃ (M+H)⁺: m/z=638.1; found 638.2.

Step 3:3-(8-Amino-2-(azetidine-1-carbonyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-(azetidine-1-carbonyl)-8-(bis(4-methoxybenzyl)amino)-5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.016 mmol),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (7 mg,0.032 mmol), sodium carbonate (5 mg, 0.048 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(5 mg, 0.006 mmol) in 4:1 THF/Water (2 mL) was stirred at 100° C. for 75mins. The reaction mixture was filtered and the organic solvent wasremoved by vacuo, the crude product was dissolved in 3 mL TFA andstirred at 80° C. for 20 mins. After TFA being removed, the crudeproduct was purified by preparative LC/MS (pH=2, acetonitrile/water withTFA) to afford the desired product as a TFA salt. LC-MS calculated forC₂₀H₁₇N₅O₂ (M+H)⁺: m/z=401.2; found 401.1.

Example 62.3-(8-amino-5-(6-hydroxypyridin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-Amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 27, Step 7; 10 mg, 0.025 mmol), (6-methoxypyridin-3-yl)boronicacid (10 mg, 0.042 mmol), cesium carbonate (17.7 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated and added MeCN (0.5 mL) and TMSCl (0.5 mL), the mixturewas heated at 80° C. for 30 min before concentrated and purified bypreparative LCMS (pH 2, acetonitrile/water with TFA) to afford thedesired product as TFA salt. LCMS calculated for C₂₃H₁₇N₈O (M+H)⁺:421.1; found 421.2.

Example 63.3-(8-amino-2-(benzo[d]oxazol-4-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(bromomethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 32, Step 5; 10 mg, 0.022 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (11 mg,0.044 mmol), cesium carbonate (17.7 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated and added TFA (1 mL), the mixture was heated at 100° C.for 30 min before concentrated and purified by preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₄H₁₆N₉O (M+H)⁺: 446.1; found 446.1.

Example 64.3-(8-amino-2-(2-fluoro-6-(1-methyl-1H-pyrazol-5-yl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-Amino-2-(2-chloro-6-fluorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 30, Step 3; 10 mg, 0.022 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.2 mg, 0.044 mmol), cesium carbonate (17.7 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated and purified by preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₇H₂₀N₁₀F (M+H)⁺: 503.2; found 503.1.

Example 65.(R)-1-(2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)-3-methylpyrrolidine-3-carboxylicAcid

The title compound was prepared using similar procedures as describedfor Example 30 with (R)-3-methylpyrrolidine-3-carboxylic acid replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₀H₂₇N₉O₂F (M+H)⁺: m/z=564.2; found564.2.

Example 66.3-(8-amino-2-(2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 30 with 6-methyl-2,6-diazaspiro[3.4]octan-5-one replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₁H₂₈N₁₀OF (M+H)⁺: m/z=575.2; found575.2.

Example 67.3-(8-amino-2-(2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 30 with hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₃₁H₂₈N₁₀OF (M+H)⁺: m/z=575.2; found575.2.

Example 68.(S)-3-(8-amino-2-(2-fluoro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 30 with (S)-3-aminopyrrolidin-2-one replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₈H₂₄N₁₀OF (M+H)⁺: m/z=535.2; found535.2.

Example 69.2-((2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)amino)acetamide

The title compound was prepared using similar procedures as describedfor Example 30 with 2-aminoacetamide replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₆H₂₂N₁₀OF (M+H)⁺: m/z=509.2; found509.2.

Example 70.3-(8-amino-2-(2-fluoro-6-((3-oxopiperazin-1-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 30 with piperazin-2-one replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₈H₂₄N₁₀OF (M+H)⁺: m/z=535.2; found535.2.

Example 71.(1S,3S)-3-((2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)amino)cyclobutane-1-carboxylicAcid

The title compound was prepared using similar procedures as describedfor Example 30 with (1s,3s)-3-aminocyclobutane-1-carboxylic acidreplacing (S)-pyrrolidine-3-carboxylic acid. The reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₂₉H₂₅N₉O₂F (M+H)⁺: m/z=550.2;found 550.2.

Example 72.3-(8-amino-2-(2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 30 with 3-amino-1-methylpyrrolidin-2-one replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₉H₂₆N₁₀OF (M+H)⁺: m/z=549.2; found549.2.

Example 73.1-(2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)azetidine-3-carbonitrile

The title compound was prepared using similar procedures as describedfor Example 30 with azetidine-3-carbonitrile replacing(S)-pyrrolidine-3-carboxylic acid. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₈H₂₂N₁₀F (M+H)⁺: m/z=517.2; found517.2.

Example 74.3-(8-amino-2-(2-fluoro-6-(((2-methyl-2H-1,2,3-triazol-4-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-amino-2-(2-fluoro-6-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 30, step 5; 10 mg, 0.02 mmol) in DCM (0.5 mL) was added2-methyl-2H-1,2,3-triazol-4-amine (4.0 mg, 0.04 mmol) then TFA (4 μL,0.08 mmol). After 1 h, sodium triacetoxyborohydride (8.5 mg, 0.04 mmol)was added to the reaction. The reaction was stirred overnight and themixture was concentrated and purified by preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₇H₂₂FN₁₂ (M+H)⁺: 533.2 found 533.2.

Example 75.(S)-3-(8-amino-2-(2-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(bis(4-methoxybenzyl)amino)-5-(pyrimidin-4-yl)-2-(2-vinylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 41, step 3; 149 mg, 0.22 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (68 mg, 0.44 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (17 mg, 21.6 μmol) and K₃PO₄ (94 mg, 0.44 mmol) in 1,4-dioxane (4mL)/water (0.8 mL) was stirred at 110° C. for 1 h. The reaction mixturewas concentrated under vacuum and the resulting residue was purifiedwith flash chromatography to give the desired product as a light yellowoil. LC-MS calculated for C₄₁H₃₅N₈O₂ (M+H)⁺: m/z=671.3; found 671.2.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-2-(2-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-(pyrimidin-4-yl)-2-(2-vinylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(60 mg, 0.089 mmol) in THF (1 mL) and water (1 mL) was added 0.157 Mosmium tetraoxide in water (0.02 mmol). After 2 min, sodiummetaperiodate (86 mg, 0.4 mmol) was added. The reaction mixture washeated at 60° C. for 1 h before quenched with sat. Na₂S₂O₃. The mixturewas extracted with DCM. The organic phase was washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford the product as a lightyellow oil. LC-MS calculated for C40H₃₃N₅O₃ (M+H)⁺: m/z=673.3; found673.3.

Step 3:(S)-3-(8-amino-2-(2-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(13.4 mg, 0.02 mmol) in DCM (0.5 mL) was added(S)-3-aminopyrrolidin-2-one (4.1 mg, 0.04 mmol) then acetic acid (4 μL,0.08 mmol). After 1 h, sodium triacetoxyborohydride (8.5 mg, 0.04 mmol)was added to the reaction. The reaction was stirred overnight and themixture was concentrated, then 0.5 mL of TFA was added to the mixtureand the mixture was heated at 100° C. for 10 min. The reaction wasconcentrated and purified by preparative LCMS (pH 2, acetonitrile/waterwith TFA) to afford the desired product as TFA salt. LCMS calculated forC₂₈H₂₅N₁₀O (M+H)⁺: 517.2 found 517.2.

Example 76.(R)-1-(2-((8-amino-6-(3-cyanophenyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)-3-methylpyrrolidine-3-carboxylicAcid

Step 1: 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

To a solution of 4-methyloxazole (0.654 g, 7.87 mmol) in heptane (3 mL)and Et₂O (1 mL) was added (1,5-cyclooctadiene)(methoxy)iridium(I) dimer(0.221 g, 0.393 mmol), 4,4′-Di-tert-butyl-2,2′-dipyridyl (0.211 g, 0.787mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.841 ml, 11.80mmol). The vial was then evacuated under high vacuum and backfilled withnitrogen. The reaction was stirred overnight, then concentrated andpurified via flash chromatography to afford the desired product as acolorless oil. LC-MS calculated for C₁₀H₁₇BNO₃ (M+H)⁺: m/z=210.1; found128.0 (as the corresponding boronic acid).

Step 2:3-(8-amino-2-(2-chloro-6-fluorobenzyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-5-bromo-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 30, Step 2; 500 mg, 1.09 mmol),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (274 mg,1.31 mmol), tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.11 mmol)and Cs₂CO₃ (712 mg, 2.185 mmol) in 1,4-dioxane (2 mL) and water (200 μl)was purged with N₂ and heated at 95° C. for 7 h. The mixture wasconcentrated and purified via flash chromatography to afford the desiredproduct as a white solid. LCMS calculated for C₂₃H₁₆N₇OClF (M+H)⁺:460.1; found 460.1.

Step 3:3-(8-amino-2-(2-fluoro-6-vinylbenzyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-2-(2-chloro-6-fluorobenzyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(101 mg, 0.22 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (68mg, 0.44 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (17 mg, 21.6 μmol) and K₃PO₄ (94 mg, 0.44 mmol) in 1,4-dioxane (2mL)/water (0.4 mL) was stirred at 110° C. for 1 h. The reaction mixturewas concentrated under vacuum and the resulting residue was purifiedwith flash chromatography to give the desired product as a colorlessoil. LC-MS calculated for C₂₅H₁₉FN₇O (M+H)⁺: m/z=452.1; found 452.2.

Step 4:3-(8-amino-2-(2-fluoro-6-formylbenzyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-amino-2-(2-fluoro-6-vinylbenzyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(40 mg, 0.089 mmol) in THF (1 mL) and water (1 mL) was added 0.157 Mosmium tetraoxide in water (0.02 mmol). After 2 min, sodiummetaperiodate (86 mg, 0.4 mmol) was added. The reaction mixture washeated at 60° C. for 1 h before quenched with sat. Na₂S₂O₃. The mixturewas extracted with DCM. The organic phase was washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford the product as a lightyellow oil. LC-MS calculated for C₂₄H₁₇FN₇O₂(M+H)⁺: m/z=454.1; found454.1.

Step 5:(R)-1-(2-((8-amino-6-(3-cyanophenyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)-3-methylpyrrolidine-3-carboxylicAcid

To a solution of3-(8-amino-2-(2-fluoro-6-formylbenzyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.02 mmol) in DCM (0.5 mL) was added(R)-3-methylpyrrolidine-3-carboxylic acid (4.8 mg, 0.04 mmol) thenacetic acid (4 μL, 0.08 mmol). After 1 h, sodium triacetoxyborohydride(8.5 mg, 0.04 mmol) was added to the reaction. The reaction was stirredovernight and the mixture was concentrated and purified by preparativeLCMS (pH 2, acetonitrile/water with TFA) to afford the desired productas TFA salt. LCMS calculated for C₃₀H₂₈FN₈O₃(M+H)⁺: 567.2 found 567.2.

Example 77.3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 32, step 2; 174 mg, 0.3 mmol), osmium(VIII) oxide (3 mg in 0.3mL water, 0.015 mmol), and sodium periodate (292 mg, 1.36 mmol) inTHF/water (1:1, 6 mL) was stirred at 65° C. for 1 h. The reactionmixture was cooled to room temperature, and extracted withdichloromethane. The combined organic layers were concentrated, andpurified by silica gel column to afford the desired product. LC-MScalculated for C₂₉H₂₄N₆O₃Br (M+H)⁺: m/z=583.1; found 583.1.

Step 2. 3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Preparation of the Grignard reagent: To a solution of1,3-difluoro-2-iodobenzene (142 mg, 0.6 mmol) in tetrahydrofuran (1 mL),isopropylmagnesium chloride solution (296 μl, 2 M) was added at −10° C.The resulting mixture was stirred for 1 h, and used directly in thefollowing step.

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(120 mg, 0.2 mmol) in THF (2 mL), the freshly prepared Grignard reagentfrom previous step was added at −10° C. The reaction mixture was stirredfor 30 min, quenched with ammonium chloride solution (4 mL), andextracted with dichloromethane. The combined organic layers wereconcentrated under vacuum and purified by a silica gel column to affordthe desired product as a racemic mixture. LC-MS calculated forC₃₅H₂₈N₆O₃BrF₂ (M+H)⁺: m/z=697.1; found 697.1.

Step 3: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(382 mg, 0.55 mmol),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (137 mg,0.65 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (17 mg, 21.6 μmol) and Cs₂CO₃ (356 mg, 1.09 mmol) in 1,4-dioxane(2 mL) and water (200 μl) was purged with N₂ and heated at 95° C. for 7h. The mixture was concentrated and purified via flash chromatography toafford the desired product as a colorless oil. LCMS calculated forC₃₉H₃₂N₇O₄F₂(M+H)⁺: 700.2; found 700.2.

Step 4:3-(8-(bis(4-methoxybenzyl)amino)-2-(chloro(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(201 mg, 0.29 mmol) in 2 mL of dichloromethane, thionyl chloride (105μl, 1.435 mmol) was added at rt. The resulting mixture was stirred for 4h, concentrated and used in next step without any further purification.LC-MS calculated for C₃₉H₃₁N₇O₃C1F₂ (M+H)⁺: m/z=718.2; found 718.2.

Step 5:3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(chloro(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(40 mg, 0.084 mmol) in 1 mL of DMSO was added ammonia solution (1 mL).The mixture was heated with microwave condition at 100° C. for 10 hbefore diluted with water and extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over MgSO₄, andconcentrated. The resulting residue was dissolved in TFA (1 mL), andstirred at 80° C. for 20 min. The reaction mixture was then cooled toroom temperature, concentrated, and basified by adding aq. NaHCO₃solution. The crude material was directly purified by a silica gelcolumn to afford the desired product as a racemic mixture. The productwas then separated with chiral HPLC using a chiral column (AM-1) and 45%EtOH in hexanes (20 mL/min) solvent system. Peak 1 was isolated, andfurther purified via preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₃H₁₇F₂N₈O (M+H)⁺: m/z=459.1; found 459.0.

Example 78.3-(8-amino-2-((2,6-difluorophenyl)(methylamino)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 77 with methyl amine (2M THF solution) replacing ammoniasolution in step 5. In addition, the replacement reaction was conductedat 70° C. for 1 h with 2 equivalents of K₂CO₃. After deprotection, theracemic product was separated with chiral HPLC using a chiral column(C2) and 30% EtOH in hexanes (20 mL/min) solvent system. Peak 2 wasisolated, and further purified via preparative LC/MS (pH=2,acetonitrile/water with TFA) to give the desired product as a TFA salt.LC-MS calculated for C₂₄H₁₉F₂N₈O (M+H)⁺: m/z=473.2; found 473.2.

Example 79.3-(8-amino-2-((2,6-difluorophenyl)((2-hydroxyethyl)amino)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 77 with 2-aminoethan-1-ol replacing ammonia solution in step5. In addition, the replacement reaction was conducted at 70° C. for 1 hwith 2 equivalents of K₂CO₃.

After deprotection, the reaction mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as TFA salt.LC-MS calculated for C₂₅H₂₁N₅O₂F₂(M+H)⁺: m/z=503.2; found 503.2.

Example 80.3-(8-amino-2-(amino(2-fluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 77 with 1-fluoro-2-iodobenzene replacing1,3-difluoro-2-iodobenzene in step 2. The final reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₂₃H₁₈N₈OF (M+H)⁺: m/z=441.1;found 441.2.

Example 81.3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 77 with2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one replacing4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole in step3. The final reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₄H₁₈N₉OF₂ (M+H)⁺: m/z=486.1; found 486.2.

Example 82.3-(8-amino-2-((3-(oxazol-5-yl)pyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 122 with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole replacing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instep 4. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₅H₁₇N₁₀O (M+H)⁺: m/z=473.1; found 473.2.

Example 83.3-(8-amino-2-(2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(13 mg, 0.022 mmol) (from Example 99, step 4),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.5 mg, 0.044 mmol), cesium carbonate (17.7 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated and dissolved in TFA (1 mL) and stirred at 100° C. for20 min. The reaction mixture was then cooled to room temperature,concentrated, and purified via preparative LC/MS (pH=2,acetonitrile/water with TFA) to give the desired product as a TFA salt.LC-MS calculated for C₂₃H₁₇F₂N₈ (M+H)⁺: m/z=443.1; found 443.2.

Example 84.(S)-3-(8-amino-2-(2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1:3-(8-(bis(4-methoxybenzyl)amino)-2-(2-fluoro-6-vinylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(Example 99, step 4; 70 mg, 0.11 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (34 mg, 0.22 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (8.5 mg, 10.8 μmol) and K₃PO₄ (47 mg, 0.22 mmol) in 1,4-dioxane (2mL)/water (0.4 mL) was stirred at 110° C. for 1 h. The reaction mixturewas concentrated under vacuum and the resulting residue was purifiedwith flash chromatography to give the desired product as a light yellowoil. LC-MS calculated for C₃₇H₃₁F₂N₆O₂(M+H)⁺: m/z=629.2; found 629.3.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-2-(2-fluoro-6-formylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-furo-6-vinylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(56 mg, 0.089 mmol) in THF (1 mL) and water (1 mL) was added 0.157 Mosmium tetraoxide in water (0.02 mmol). After 2 min, sodiummetaperiodate (86 mg, 0.4 mmol) was added. The reaction mixture washeated at 60° C. for 1 h before quenched with sat. Na₂S₂O₃. The mixturewas extracted with DCM. The organic phase was washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford the product as a lightyellow oil. LC-MS calculated for C₃₆H₂₉F₂N₆O₃(M+H)⁺: m/z=631.2; found631.1.

Step 3:(S)-3-(8-amino-2-(2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-fluoro-6-formylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(10 mg, 0.02 mmol) in DCM (0.5 mL) was added(S)-3-amino-1-methylpyrrolidin-2-one (4.6 mg, 0.04 mmol) then aceticacid (4 μL, 0.08 mmol). After 1 h, sodium triacetoxyborohydride (8.5 mg,0.04 mmol) was added to the reaction. The reaction was stirred overnightand the mixture was concentrated, then 0.5 mL of TFA was added to themixture and the mixture was heated at 100° C. for 10 min. The reactionwas concentrated and purified by preparative LCMS (pH 2,acetonitrile/water with TFA) to afford the desired product as TFA salt.LCMS calculated for C₂₅H₂₃N₈OF₂ (M+H)⁺: 489.2 found 489.2.

Example 85.3-(8-amino-2-(2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

The title compound was prepared using similar procedures as describedfor Example 84 with 6-methyl-2,6-diazaspiro[3.4]octan-5-one replacing(S)-3-amino-1-methylpyrrolidin-2-one in step 3. The reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as TFA salt. LC-MS calculated for C₂₇H₂₅N₈OF₂ (M+H)⁺: m/z=515.2;found 515.2.

Example 86.3-(8-amino-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1:6-bromo-N,N-bis(4-methoxybenzyl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

To a flask charged with 2-(pyridin-2-yl)acetic acid (164 mg, 1.2 mmol),HATU (708 mg, 1.9 mmol) in CH₂Cl₂ (10 ml) was added1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (400 mg, 0.62 mmol), followed by DIEA(0.65 ml, 3.72 mmol). After stirring at room temperature for 6 h, LCMSshowed completion of reaction. The reaction mixture was diluted with DCMand water. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified with flashchromatography to give the desired product. LC-MS calculated forC₂₇H₂₆BrN₆O₂ (M+H)⁺: m/z=545.1; found 545.2.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A flask charged with6-bromo-N,N-bis(4-methoxybenzyl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(108 mg, 0.2 mmol), (3-cyano-2-fluorophenyl)boronic acid (49.7 mg, 0.35mmol), Cs₂CO₃ (134 mg, 0.41 mmol), Pd-tetrakis (23 mg, 0.02 mmol),1,4-dioxane (2 ml) and water (0.2 ml) was evacuated under vacuum andrefilled with N₂ (repeated three times). The mixture was heated at 100°C. for 8 h. LCMS showed total completion of reaction. The reactionmixture was diluted with DCM and water. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified with flash chromatography to give the desiredproduct. LC-MS calculated for C₃₄H₂₉FN₇O₂(M+H)⁺: m/z=586.2; found 586.2.

Step 3:3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(146 mg, 0.25 mmol) in 3 mL of dichloromethane,1-bromopyrrolidine-2,5-dione (46 mg, 0.25 mmol) was added at 0° C. Theresulting mixture was stirred for 16 h before concentrated and purifiedby silica gel column to afford the desired product. LC-MS calculated forC₃₄H₂₈FBrN₇O₂ (M+H)⁺: m/z=664.1; found 664.2.

Step 4:3-(8-amino-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(15 mg, 0.022 mmol),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (Example76, step 1; 9.1 mg, 0.044 mmol), cesium carbonate (17.7 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated, then 0.5 mL of TFA was added to the mixture and themixture was heated at 100° C. for 10 min. The reaction was concentratedand purified by preparative LCMS (pH 2, acetonitrile/water with TFA) toafford the desired product as TFA salt. LCMS calculated for C₂₂H₁₆N₈OF(M+H)⁺: 427.1; found 427.1.

Example 87.3-(8-amino-5-(4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

The title compound was prepared using similar procedures as describedfor Example 86 with4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoroethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole(Example 35, step 3) replacing4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole in step4. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₄H₁₈N₈O₂F₃(M+H)⁺: m/z=507.1; found 507.2.

Example 88.3-(8-amino-5-(2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1: 2,2,2-trifluoro-1-(2-methyloxazol-4-yl)ethan-1-ol

To a solution of 2-methyloxazole-4-carbaldehyde (300 mg, 2.70 mmol) indry THF (10 ml) was added trimethyl(trifluoromethyl)silane (797 μl, 5.40mmol) dropwise followed by adding CsF (820 mg, 5.40 mmol). Afterstirring at rt for 30 min, TBAF (1M THF solution, 2.70 mmol) was added,and the reaction mixture was stirred further for 10 min before quenchedwith sat. NH₄Cl. The mixture was extracted twice with EtOAc, Thecombined organic layers were washed with sat. NaCl solution, dried overNa₂SO₄, filtered, and concentrated to afford the crude product as abrown oil, which was used directly in next step without furtherpurification. LC-MS calculated for C₆H7F₃NO₂ (M+H)⁺: m/z=182.0; found182.0.

Step 2:4-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-2-methyloxazole

In a flame dried round-bottomed flask equipped with a magnetic stir bar,a solution of 2,2,2-trifluoro-1-(2-methyloxazol-4-yl)ethan-1-ol (1.24 g,6.87 mmol) in DCM (10 mL) was treated at rt withtert-butylchlorodimethylsilane (1.13 g, 6.88 mmol) followed by imidazole(0.47 g, 6.87 mmol) and the resulting suspension was stirred for 1 h atit. After completion, water was added to quench the reaction. Themixture was then extracted with EtOAc, the organic layers were driedover Na₂SO₄, filtered and the solvent was removed under reducedpressure. The residue was purified with flash chromatography to give thedesired product. LC-MS calculated for C₁₂H₂₁F₃NO₂Si (M+H)⁺: m/z=296.1;found 296.1.

Step 3:4-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

In a flame dried round-bottomed flask equipped with a magnetic stir bar,was charged with (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (60 mg,0.09 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (834 mg, 3.0 mmol),and pentane (4.0 mL). The mixture was stirred at room temperature for 10min. Then 4,4′-di-tert-butyl-2,2′-dipyridyl (48 mg, 0.18 mmol) was addedto this mixture and reaction stirred for additional 20 min.4-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-2-methyloxazole(708 mg, 2.4 mmol) dissolved in Et₂O (4 mL) was added to the activecatalyst mixture. The reaction was stirred at room temperature untilcompletion. Solvent was removed under reduced pressure, and the crudematerial was purified with flash chromatography to give the desiredproduct. LC-MS calculated for the corresponding boronic acidC₁₂H₂₂BF₃NO₄Si (M+H)⁺: m/z=340.2; found 340.1.

Step 4:3-(8-amino-5-(2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(Example 86, step 3; 15 mg, 0.022 mmol),4-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole(18 mg, 0.044 mmol), cesium carbonate (17.7 mg, 0.116 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.26 mg, 2.88 μmol) (XPhos Pd G2) in 1,4-dioxane (500 μl) and water(100 μl) was purged with N₂ and heated at 95° C. for 1 h. The mixturewas concentrated, then 0.5 mL of TFA was added to the mixture and themixture was heated at 100° C. for 10 min. The reaction was concentratedand purified by preparative LCMS (pH 2, acetonitrile/water with TFA) toafford the desired product as TFA salt. LCMS calculated forC₂₄H₁₇N₈O₂F₄(M+H)⁺: 525.1; found 525.1.

Example 89.3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

The title compound was prepared using similar procedures as describedfor Example 86 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onereplacing4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole in step4. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₄H₁₈N₈OF (M+H)⁺: m/z=453.1; found 453.2.

Example 90.3-(8-amino-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1: tert-butyl2-((8-(bis(4-methoxybenzyl)amino)-6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)pyrrolidine-1-carboxylate

To a solution of1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (1.80 g, 2.79 mmol),2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (704 mg, 3.07mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate (TBTU, 1.35 g, 4.19 mmol) in dichloromethane (20 mL)was added N,N-diisopropylethylamine (0.980 mL, 5.58 mmol) dropwise. Theresultant mixture was stirred at room temp overnight. The resultingmixture was filtered, concentrated under reduced pressure, and purifiedby Biotage Isolera (with 50 g silica gel column) eluting with 0-50%EtOAc/Hexane to give the product. LCMS calculated for C₃₁H₃₈BrN₆O₄ ⁺(M+H)⁺: m/z=637.2, 639.2; found: 637.3, 639.3.

Step 2: tert-butyl2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl2-((8-(bis(4-methoxybenzyl)amino)-6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)pyrrolidine-1-carboxylate(1.20 g, 1.88 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2) (0.148 g, 0.188 mmol), sodium carbonate (0.299 g, 2.82mmol) and (3-cyano-2-fluorophenyl)boronic acid (0.310 g, 1.88 mmol) in1,4-dioxane (17 ml)/Water (1.7 ml) in a 40 mL vial was heated at 90° C.overnight. The mixture was diluted with water and extracted with EtOAc(×3). The organic extracts were dried (anhyd. Na₂SO₄) and concentratedunder reduced pressure. The residue was purified by Biotage Isolera(with 50 g silica gel column) eluting with 0-50% EtOAc/Hexane to givethe product. LCMS calculated for C₃₈H₄₁FN₇O₄ ⁺ (M+H)⁺: m/z=678.3; found:678.4.

Step 3:3-(8-amino-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of tert-butyl2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)pyrrolidine-1-carboxylate(1.13 g, 1.67 mmol) in TFA (30 mL) was heated at 70° C. for 1 h. Aftercooling to room temperature, TFA was evaporated, and the residue wasdiluted with 1 N NaOH (200 mL). The resultant mixture was extracted withDCM (×3) and the combined organic extracts were dried (anhyd. Na₂SO₄)and concentrated under reduced pressure to afford the product usingwithout further purification. LCMS calculated for C₁₇H₁₇FN₇ ⁺ (M+H)⁺:m/z=338.1; found: 338.1.

Step 4:3-(8-amino-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of3-(8-amino-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(14 mg, 0.043 mmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride (6.0mg, 0.033 mmol) and triethylamine (14 μL, 0.099 mmol) in DCM (0.25 ml)was stirred at room temp for 2 h. The resultant mixture was diluted withacetonitrile, filtered, and purified by preparative LC/MS (pH=2,acetonitrile/water with TFA) to afford the desired product as a TFAsalt. LCMS calculated for C₂₁H₂₁FN₉O₂S⁺ (M+H)⁺: m/z=482.1; found: 482.0.

Example 91.3-(2-(2-((1-acetylpiperidin-4-yl)methyl)-6-fluorobenzyl)-8-amino-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1: tert-butyl4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzylidene)piperidine-1-carboxylate

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(193 mg, 0.303 mmol) (from Example 99, step 4), XPhos Pd G2 (23.84 mg,0.030 mmol), potassium phosphate (193 mg, 0.909 mmol) and tert-butyl4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate(98.1 mg, 0.303 mmol) in 1,4-dioxane (2.75 mL)/Water (0.550 mL) in a 40mL vial was flushed with nitrogen for ca. 2 min and heated at 120° C.for 3 h. After cooling to room temp, the mixture was diluted with waterand extracted with DCM (×3). The combined organic extracts were dried(anhyd. Na₂SO₄), concentrated under reduced pressure, and purified byBiotage Isolera (with 50 g silica gel column) eluting with 0-100%EtOAc/Hexane to give the product. LCMS calculated for C₄₆H₄₆F₂N₇O₄ ⁺(M+H)⁺: m/z=798.4; found: 798.4.

Step 2: tert-butyl4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzylidene)piperidine-1-carboxylate(151 mg, 0.188 mmol) and Pd(OH)2/C (20% wt, 26 mg, 0.038 mmol) in MeOH(2 mL)/DCM (1.000 mL)) in a 20 mL vial was stirred at room temp under H₂balloon overnight. The resultant mixture was filtered, concentratedunder reduced pressure, and used without further purification. LCMScalculated for C₄₆H₄₈F₂N₇O₄ ⁺ (M+H)⁺: m/z=800.4; found: 800.5.

Step 3:2-fluoro-3-(2-(2-fluoro-6-(piperidin-4-ylmethyl)benzyl)-8-((4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of tert-butyl4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)piperidine-1-carboxylate(130 mg, 0.163 mmol) in DCM (10 mL) was added TFA (5.0 mL) dropwise. Theresultant mixture was stirred and room temp for 30 min and transferredto a separated funnel with DCM and add 1N NaOH (ca. 200 mL) was added.The layers were separated and the aqueous layer was extracted with DCM(×2). The combined organic extracts were dried (anhyd. Na₂SO₄),concentrated under reduced pressure, and used without furtherpurification. LCMS calculated for C₃₃H₃₂F₂N₇O⁺ (M+H)⁺: m/z=580.3; found:580.3.

Step 4:3-(2-(2-((1-acetylpiperidin-4-yl)methyl)-6-fluorobenzyl)-8-((4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of2-fluoro-3-(2-(2-fluoro-6-(piperidin-4-ylmethyl)benzyl)-8-((4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(14 mg, 0.025 mmol) and acetyl chloride (25 μL, 0.025 mmol, 1M in DCM)in DCM (0.5 mL) was added triethylamine (10.5 μL, 0.0750 mmol). Theresultant mixture was stirred at room temp for 1 h, filtered, andconcentrated under reduced pressure. The residue was added TFA (0.5 mL)stirred 70 OC for 1 h. The resulting mixture was diluted withacetonitrile, filtered, and purified by preparative LC/MS (pH=2,acetonitrile/water with TFA) to afford the desired product as a TFAsalt. LCMS calculated for C₂₇H₂₆F₂N₇O⁺ (M+H)⁺: m/z=502.2; found: 502.1.

Example 92.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(1-ethyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

Step 1: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of 1,3-difluoro-2-iodobenzene (0.822 g, 3.42 mmol) in THF(2 mL) was added isopropylmagnesium chloride lithium chloride complexsolution (1.3 M, 2.3 mL, 3.0 mmol) dropwise at 0° C. The reactionmixture was stirred at 0° C. for 30 minutes. A solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.432 g, 0.856 mmol) (from Example 40, step 1) in THF (2 mL) was addeddropwise and the reaction mixture was stirred at 0° C. for 1 h. Thereaction mixture was then quenched with saturated aqueous NH₄Cl solutionand diluted with DCM. The layers were separated, the aqueous layer wasextracted with DCM, and the combined organic fractions were dried overMgSO₄, filtered and concentrated. The crude residue was purified usingflash chromatography to give the desired product (0.301 g, 57%). LC-MScalculated for C₃₅H₂₉F₂N₆O₃(M+H)⁺: m/z=619.2; found 619.2.

Step 2: 3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.301 g, 0.487 mmol) in DCM (2 mL) was added a solution of NBS (0.087g, 0.487 mmol) in DCM (2 mL) dropwise at 0° C., The reaction mixture wasstirred at 0° C. for 1 h. The reaction mixture was concentrated, and theresulting residue was purified using flash chromatography to give thedesired product (0.339 g, 99%). LC-MS calculated for C₃₅H₂₈BrF₂N₆O₃(M+H)⁺: m/z=697.1; found 697.1.

Step 3: 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(1-ethyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.210 g, 0.301 mmol),1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.267 g, 1.20 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.071 g, 0.090 mmol) in dioxane (2.50 mL) and water (0.50 mL) wasadded potassium phosphate tribasic (0.320 g, 1.51 mmol). The reactionmixture was stirred at 100° C. for 2 h. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was dissolvedin TFA (5 mL) and heated to 80° C. for 20 minutes. The reaction mixturewas then cooled to room temperature, concentrated, and basified byadding aqueous NaHCO₃ solution. The crude material was directly purifiedby a silica gel column to afford the desired product (110 mg, 77%) as aracemic mixture. The product was then separated with chiral SFC using achiral column (ES Industries ChromegaChiral CC4) and 25% MeOH in CO₂ (85mL/min) solvent system. Peak 1 was isolated, and further purified usingpreparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₄H₁₉F₂N₈O (M+H)⁺:m/z=473.2; found 473.2.

Example 93.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(1-ethyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 92. The product was separated with chiral SFC using a chiralcolumn (ES Industries ChromegaChiral CC4) and 25% MeOH in CO₂ (85mL/min) solvent system. Peak 2 was isolated, and further purified usingpreparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₄H₁₉F₂N₈O (M+H)⁺:m/z=473.2; found 473.2.

Example 94.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.518 g, 0.638 mmol) (from example 92, step 2),2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.346 g, 1.48 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.058 g, 0.074 mmol) in dioxane (3.0 mL) and water (0.60 mL) wasadded potassium phosphate tribasic (0.472 g, 2.23 mmol). The reactionmixture was stirred at 90° C. for 1 h. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was dissolvedin TFA (5 mL) and heated to 80° C. for 20 minutes. The reaction mixturewas then cooled to room temperature, concentrated, and basified byadding aqueous NaHCO₃ solution. The crude material was directly purifiedby a silica gel column to afford the desired product (257 mg, 72%) as aracemic mixture. The product was then separated with chiral HPLC using achiral column (Phenomenex Lux 5 um Cellulose-2, 21.1×250 mm) and 35%EtOH in Hexanes (20 mL/min) solvent system. Peak 1 was isolated, andfurther purified using preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₆H₂₀F₂N₇O (M+H)⁺: m/z=484.2; found 484.2. ¹H NMR (500 MHz, DMSO-d₆) δ7.92 (s, 21H), 7.85 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.0 Hz,1H), 7.53-7.40 (m, 4H), 7.10 (t, J=8.4 Hz, 2H), 6.27 (s, 1H), 2.51 (s,6H).

Example 95.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 94. The product was then separated with chiral HPLC using achiral column (Phenomenex Lux 5 um Cellulose-2, 21.1×250 mm) and 35%EtOH in Hexanes (20 mL/min) solvent system. Peak 2 was isolated, andfurther purified using preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₆H₂₀F₂N₇O (M+H)⁺: m/z=484.2; found 484.2. ¹H NMR (500 MHz, DMSO-d₆) δ7.92 (s, 2H), 7.85 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.0 Hz,1H), 7.53-7.40 (m, 4H1), 7.10 (t, J=8.4 Hz, 2H), 6.27 (s, 1H), 2.51 (s,61H1).

Example 96.3-(2-((1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)-4-amino-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(4-amino-2-(bromomethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(4-amino-2-(hydroxymethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.48 g, 1.40 mmol) (from Example 13, step 2) in dry THF (10 ml) wasadded PBr₃ (1.14 g, 4.19 mmol) dropwise at room temperature. Thereaction mixture was stirred rapidly at 60° C. for 5 hours. The reactionmixture was cooled and quenched with saturated aqueous NaHCO₃ solution.The layers were separated, the aqueous layer was extracted with DCM, andthe combined organic fractions were dried over MgSO₄, filtered andconcentrated. The crude material was directly purified by a silica gelcolumn (0 to 100% ethyl acetate/hexanes) to afford the desired product(0.48 g, 84%). LC-MS calculated for C₁₈H₁₃BrN₇ (M+H)⁺: m/z=406.0; found406.1.

Step 2:3-(2-((1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)-4-amino-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(4-amino-2-(bromomethyl)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.015 g, 0.037 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridine(0.029 g, 0.074 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.006 g, 0.007 mmol) in dioxane (0.3 mL) and water (0.06 mL) wasadded potassium phosphate tribasic (0.024 g, 0.111 mmol). The reactionmixture was stirred at 90° C. for 1 h. The reaction mixture was thendiluted with water (0.3 ml) and THF (0.3 ml). NaOH (25 mg) was added tothe vial and the vial was stirred at room temperature for 30 minutes.The reaction mixture was diluted with DMF (4 ml) and purified withprep-LCMS (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₅H₁₈N₉(M+H)⁺: m/z=444.2; found 444.2.

Example 97.3-(8-amino-2-((2-(difluoromethoxy)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of 1-(difluoromethoxy)-3-fluoro-2-iodobenzene (74 mg, 0.26mmol) in tetrahydrofuran (0.2 mL), isopropylmagnesium chloride lithiumchloride (0.2 ml, 1.3 M solution) was added at −10° C., and theresulting mixture was stirred for 1 hour before a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(20 mg, 0.034 mmol) (from Example 49 step 8) in THF (0.2 mL) was addedat −10° C. The reaction mixture was stirred for 30 min, quenched withammonium chloride solution (1 mL), and extracted with dichloromethane.The combined organic layers were concentrated under vacuum. Theresulting material was dissolved in TFA (1 mL), and stirred at 80° C.for 20 min. The reaction mixture was then cooled to room temperature,concentrated, and basified by adding aqueous NaHCO₃ solution. The crudematerial was directly purified by a silica gel column to afford thedesired product (16 mg, 94%) as a racemic mixture. The product was thenseparated with chiral HPLC using a chiral column (Phenomenex Lux 5 umCellulose-4, 21.1×250 mm) and 45% EtOH in Hexanes (20 mL/min) solventsystem. Peak 1 was isolated, and further purified using preparativeLC/MS (pH=2, acetonitrile/water with TFA) to give the desired product asa TFA salt. LC-MS calculated for C₂₄H₁₆F₃N₈O₂ (M+H)⁺: m/z=505.1; found505.1.

Example 98.3-(8-amino-2-((2-(difluoromethoxy)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 97. The racemic product was separated with chiral HPLC using achiral column (Phenomenex Lux 5 um Cellulose-4, 21.1×250 mm) and 45%EtOH in Hexanes (20 mL/min) solvent system. Peak 2 was isolated, andfurther purified using preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₄H₁₆F₃N₈O₂(M+H)⁺: m/z=505.1; found 505.1.

Example 99.3-(8-amino-2-(2-fluoro-6-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1: 6-bromo-N²,N²-bis(4-methoxybenzyl)pyrazine-2,3-diamine

To a stirred suspension of 3,5-dibromopyrazin-2-amine (6 g, 23.25 mmol)and bis(4-methoxybenzyl)amine (6.72 g, 25.6 mmol) in n-butanol (23.25ml) at room temperature was added N,N-diisopropylethylamine (8.18 ml,46.5 mmol). The reaction mixture was heated at 120° C. for 72 hours. Thereaction mixture was cooled to room temperature. The resulting slurrywas stirred at room temperature for 1 hour. The suspension was filteredto remove the excess 3,5-dibromopyrazin-2-amine. The filtrate wasconcentrated in vacuo. The residue was purified by Biotage Isolera (with330 g silica gel column) eluting with 0-50% EtOAc/Hexane to give theproduct as a brown very viscous oil (6.282 g, 77% yield). LC-MScalculated for C₂₀H₂₂BrN₄O₂(M+H)⁺: m/z=429.1; found 429.4.

Step 2: 1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (8.88 g, 41.3 mmol)(from Example 14 step 2) in dichloromethane (300 ml) was added6-bromo-N²,N²-bis(4-methoxybenzyl)pyrazine-2,3-diamine (16.1 g, 37.5mmol). The resulting solution was stirred at room temperature overnight.The mixture was concentrated and purified with a silica gel column(eluting with a gradient of 0-100% ethyl acetate in hexanes then 0-20%methanol in DCM) to give the desired product (16 g, 66%). LC-MScalculated for C₂₀H₂₃BrN₅O₂ (M−C₉H₁₁O₃S)⁺: m/z=444.1; found 444.1.

Step 3:6-bromo-2-(2-chloro-6-fluorobenzyl)-N,N-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

To a solution of1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (2.5 g, 3.88 mmol),N,N-diisopropylethylamine (7.52 g, 58.2 mmol), and2-(2-chloro-6-fluorophenyl)acetic acid (2.93 g, 15.5 mmol) in DMF (20ml) was added (3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.36 g, 1.86 mmol). The reaction mixture was stirred at roomtemperature for 1 hour. The solvent was removed under reduced pressureand the crude residue was diluted with water and dichloromethane. Thelayers were separated and the aqueous layer extracted withdichloromethane. The combined organic fractions were filtered over aplug of magnesium sulfate and concentrated. Purification by automaticflash column chromatography afforded the desired product (1.34 g, 58%).LC-MS calculated for C₂₈H₂₅BrClFN₅O₂(M+H)⁺: m/z=596.1; found 596.1.

Step 4:3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of6-bromo-2-(2-chloro-6-fluorobenzyl)-N,N-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(1.34 g, 2.25 mmol),2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.72 g, 2.92 mmol), potassium phosphate tribasic (1.43 g, 6.73 mmol) indioxane (10 ml) and water (2 ml) was addedtetrakis(triphenylphosphine)palladium(0) (0.39 g, 0.38 mmol). Thereaction mixture was sparged with nitrogen gas for five minutes, sealedand heated to 90° C. for 1 hour. The reaction mixture was cooled to roomtemperature, the solvent was removed under reduced pressure, and thecrude residue was diluted with water and dichloromethane. The layerswere separated and the aqueous layer extracted with dichloromethane. Thecombined organic fractions were filtered over a plug of magnesiumsulfate and concentrated. Purification by automatic flash columnchromatography afforded the desired product (0.886 g, 62%). LC-MScalculated for C₃₅H₂₈ClF₂N₆O₂ (M+H)⁺: m/z=637.2; found 637.2.

Step 5:1-methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)-1H-pyrazole

A vial was charged with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.5 g, 2.58mmol), 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (0.660 g, 2.58mmol), cesium carbonate (2.52 g, 7.73 mmol), and DMF (6.44 ml). Thereaction mixture was stirred at 60° C. for one hour. The solvent wasstripped and the crude residue was diluted with water anddichloromethane. The layers were separated and the aqueous layerextracted with dichloromethane. The combined organic fractions werefiltered over a plug of magnesium sulfate and concentrated. The crudematerial was used in the next step without further purification (0.74 g,99%). LC-MS calculated for C₁₄H₂₂BN₄O₂(M+H)⁺: m/z=289.2; found 289.1.

Step 6:3-(8-amino-2-(2-fluoro-6-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.010 g, 0.016 mmol),1-methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)-1H-pyrazole(0.009 g, 0.031 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.002 g, 0.003 mmol) in dioxane (0.3 mL) and water (0.06 mL) wasadded potassium phosphate tribasic (0.010 g, 0.047 mmol). The reactionmixture was stirred at 90° C. for 1 h. The reaction mixture was thendiluted with water and dichloromethane. The layers were separated andthe aqueous layer extracted with dichloromethane. The combined organicfractions were concentrated under vacuum. The resulting material wasdissolved in TFA (1 mL), and stirred at 80° C. for 20 min. The reactionmixture was then cooled to room temperature, diluted with DMF (4 ml) andpurified using preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired product as a TFA salt. LC-MS calculated for C₂₇H₂₁F₂N₁₀(M+H)⁺: m/z=523.2; found 523.2.

Example 100.3-(8-amino-2-((2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazol[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

Step 1: 1-(bromomethyl)-3-fluoro-2-iodobenzene

A round bottom flask was charged with (3-fluoro-2-iodophenyl)methanol(0.445 g, 1.766 mmol), carbon tetrabromide (0.703 g, 2.119 mmol),triphenylphosphine (0.556 g, 2.119 mmol), N,N-diisopropylethylamine(0.617 ml, 3.53 mmol), and dichloromethane (17.66 ml). The reactionmixture was stirred overnight at room temperature. The solvent wasstripped and the crude residue was purified by automatic flash columnchromatography to afford the desired product (0.554 g, 99%).

Step 2: 1-(3-fluoro-2-iodophenyl)-N,N-dimethylmethanamine

A round bottom flask was charged with1-(bromomethyl)-3-fluoro-2-iodobenzene (0.554 g, 1.77 mmol),dichloromethane (17 ml), and dimethylamine solution (4.41 ml, 2M inethanol). The reaction mixture was stirred at room temperature for 1hour. The solvent was stripped and the crude residue was purified byautomatic flash column chromatography to afford the desired product(0.176 g, 36%). LC-MS calculated for C₉H₁₂FIN (M+H)⁺: m/z=280.0; found280.1.

Step 3: 3-(8-amino-2-((2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of 1-(3-fluoro-2-iodophenyl)-N,N-dimethylmethanamine(0.179 g, 0.642 mmol) in tetrahydrofuran (1.5 mL), isopropylmagnesiumchloride lithium chloride (0.726 ml, 1.3 M solution) was added at −10°C., and the resulting mixture was stirred for 1 h before a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.220 mg, 0.378 mmol) (from Example 49 step 8) in THF (1.5 mL) wasadded at −10° C. The reaction mixture was stirred for 60 min, thenquenched with ammonium chloride solution (3 mL), and extracted withdichloromethane. The combined organic layers were concentrated undervacuum. The resulting material was dissolved in TFA (3 mL), and stirredat 80° C. for 20 min. The reaction mixture was then cooled to roomtemperature, concentrated, and basified by adding aqueous NaHCO₃solution. The crude material was directly purified by a silica gelcolumn to afford the desired product (87 mg, 47%) as a racemic mixture.The product was then separated with chiral HPLC using a chiral column(Phenomenex Lux 5 um Cellulose-1, 21.1×250 mm) and 30% EtOH in Hexanes(20 mL/min) solvent system. Peak 1 was isolated, and further purifiedusing preparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₆H₂₃FN₉O (M+H)⁺:m/z=496.2; found 496.2.

Example 101.3-(8-amino-2-((2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 100. The product was then separated with chiral HPLC using achiral column (Phenomenex Lux 5 um Cellulose-1, 21.1×250 mm) and 30%EtOH in Hexanes (20 mL/min) solvent system. Peak 2 was isolated, andfurther purified using preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₆H₂₃FN₉O (M+H)⁺: m/z=496.2; found 496.2.

Example 102.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.43 g, 0.062 mmol) (from example 92, step 2), tert-butyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.076 g, 0.246 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.010 g, 0.012 mmol) in dioxane (0.5 mL) and water (0.1 mL) wasadded potassium phosphate tribasic (0.065 g, 0.308 mmol). The reactionmixture was stirred at 100° C. for 1 hour. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was dissolvedin TFA (2 mL) and heated to 80° C. for 20 minutes. The reaction mixturewas then cooled to room temperature, concentrated, and basified byadding aqueous NaHCO₃ solution. The crude material was directly purifiedby a silica gel column to afford the desired product (8 mg, 29%) as aracemic mixture. The product was then separated with chiral HPLC using achiral column (Phenomenex Lux 5 um Cellulose-4, 21.1×250 mm) and 40%EtOH in Hexanes (20 mL/min) solvent system. Peak 1 was isolated, andfurther purified using preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₃H₁₇F₂N₈O (M+H)⁺: m/z=459.1; found 459.2.

Example 103.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 102. The product was separated with chiral HPLC using a chiralcolumn (Phenomenex Lux 5 um Cellulose-4, 21.1×250 mm) and 40% EtOH inHexanes (20 mL/min) solvent system. Peak 2 was isolated, and furtherpurified using preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired product as a TFA salt. LC-MS calculated for C₂₃H₁₇F₂N₈O(M+H)⁺: m/z=459.1; found 459.2.

Example 104.3-(5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.015 g, 0.022 mmol) (from example 92, step 2),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine(0.021 g, 0.086 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.005 g, 0.006 mmol) in dioxane (0.3 mL) and water (0.06 mL) wasadded potassium phosphate tribasic (0.023 g, 0.108 mmol). The reactionmixture was stirred at 100° C. for 1 hour. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was dissolvedin TFA (1 mL) and heated to 80° C. for 20 minutes. The reaction mixturewas then cooled to room temperature, diluted with DMF (4 ml), andpurified using preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired racemic product as a TFA salt. LC-MS calculated forC₂₅H₁₆F₂N₉O (M+H)⁺: m/z=496.1; found 496.1.

Example 105.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(oxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.43 g, 0.062 mmol) (from example 92, step 2),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (0.048 g, 0.246mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.010 g, 0.012 mmol) in dioxane (0.5 mL) and water (0.1 mL) wasadded potassium phosphate tribasic (0.065 g, 0.308 mmol). The reactionmixture was stirred at 100° C. for 1 hour. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was dissolvedin TFA (2 mL) and heated to 80° C. for 20 minutes. The reaction mixturewas then cooled to room temperature, concentrated, and basified byadding aqueous NaHCO₃ solution. The crude material was directly purifiedby a silica gel column to afford the desired product (6 mg, 22%) as aracemic mixture. The product was then separated with chiral SFC using achiral column (ES Industries CC4 5 um 20×250 mm) and 35% MeOH in CO₂ (65mL/min) solvent system. Peak 1 was isolated, and further purified usingpreparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₂H₁₄F₂N₇O₂(M+H)⁺:m/z=446.1; found 446.1.

Example 106.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(oxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 105. The product was then separated with chiral SFC using achiral column (ES Industries CC4 5 um 20×250 mm) and 35% MeOH in CO₂ (65mL/min) solvent system. Peak 2 was isolated, and further purified usingpreparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₂H₁₄F₂N₇O₂(M+H)⁺:m/z=446.1; found 446.1.

Example 107.3-(8-amino-2-(2-fluoro-6-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.01 g, 0.016 mmol) (from Example 99, step 4),2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine(0.009 g, 0.031 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.002 g, 0.003 mmol) in dioxane (0.3 mL) and water (0.06 mL) wasadded potassium phosphate tribasic (0.010 g, 0.047 mmol). The reactionmixture was stirred at 90° C. for 1 hour. The reaction mixture was thendiluted with water and dichloromethane. The layers were separated andthe aqueous layer extracted with dichloromethane. The combined organicfractions were concentrated under vacuum. The resulting material wasdissolved in TFA (1 mL), and stirred at 80° C. for 20 min. The reactionmixture was then cooled to room temperature, diluted with DMF (4 ml) andpurified using preparative LC/MS (pH=2, acetonitrile/water with TFA) togive the desired product as a TFA salt. LC-MS calculated for C₂₈H₂₀F₂N₉(M+H)⁺: m/z=520.2; found 520.1.

Example 108.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.43 g, 0.062 mmol) (from example 92, step 2),3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.054g, 0.246 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.010 g, 0.012 mmol) in dioxane (0.5 mL) and water (0.1 mL) wasadded potassium phosphate tribasic (0.065 g, 0.308 mmol). The reactionmixture was stirred at 100° C. for 1 hour. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was dissolvedin TFA (2 mL) and heated to 80° C. for 20 minutes. The reaction mixturewas then cooled to room temperature, concentrated, and basified byadding aqueous NaHCO₃ solution. The crude material was directly purifiedby a silica gel column to afford the desired product (8 mg, 28%) as aracemic mixture. The product was then separated with chiral SFC using achiral column (ES Industries CC4 5 um 20×250 mm) and 35% MeOH in CO₂ (65mL/min) solvent system. Peak 1 was isolated, and further purified usingpreparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₅H₁₈F₂N₇O (M+H)⁺:m/z=470.2; found 470.2.

Example 109.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 108. The product was then separated with chiral SFC using achiral column (ES Industries CC4 5 um 20×250 mm) and 35% MeOH in CO₂ (65mL/min) solvent system. Peak 2 was isolated, and further purified usingpreparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₅H₁₈F₂N₇O (M+H)⁺:m/z=470.2; found 470.2.

Example 110.3-(8-amino-2-((2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

Step 1: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2-chloro-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of 1-chloro-3-fluoro-2-iodobenzene (0.335 g, 1.30 mmol) intetrahydrofuran (1.5 mL), isopropylmagnesium chloride lithium chloride(0.878 ml, 1.3 M solution) was added at −10° C., and the resultingmixture was stirred for 1 hour before a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.190 g, 0.326 mmol) (from Example 49 step 8) in THF (1.5 mL) was addedat −10° C. The reaction mixture was stirred for 60 minutes, thenquenched with ammonium chloride solution (3 mL), and extracted withdichloromethane. The combined organic layers were concentrated undervacuum. The crude material was directly purified by a silica gel columnto afford the desired product (147 mg, 63%) as a racemic mixture. LC-MScalculated for C₃₉H₃₁ClFN₈O₃(M+H)⁺: m/z=713.2; found 713.3.

Step 2: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2-fluoro-6-vinylphenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-((2-chloro-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.212 g, 0.297 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.055 g, 0.357 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.023 g, 0.030 mmol) in dioxane (2.5 mL) and water (0.5 mL) wasadded potassium phosphate tribasic (0.126 g, 0.595 mmol). The reactionmixture was stirred at 100° C. for 1 h. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was directlypurified by a silica gel column to afford the desired product (0.195 mg,93%). LC-MS calculated for C₄₁H₃₄FN₈O₃(M+H)⁺: m/z=705.3; found 705.4.

Step 3: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2-fluoro-6-formylphenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-((2-fluoro-6-vinylphenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.195 g, 0.277 mmol), THF (2.5 ml), water (2.5 ml), sodium periodate(0.266 g, 1.245 mmol), and osmium tetroxide solution (0.176 ml, 4% inwater). The mixture was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with water and dichloromethane. The layerswere separated and the aqueous layer extracted with dichloromethane. Thecombined organic fractions were filtered over a plug of magnesiumsulfate and purified by automatic flash column chromatography to affordthe product (0.135 g, 69%). LC-MS calculated for C₄₀H₃₂FN₈O₄(M+H)⁺:m/z=707.2; found 707.3.

Step 4: 3-(8-amino-2-((2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 1

A vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-((2-fluoro-6-formylphenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.013 g, 0.018 mmol), pyrrolidine (0.013 g, 0.178 mmol), acetic acid(2.041 μl, 0.036 mmol), dichloromethane (0.4 ml), and sodium borohydride(1.3 mg, 0.036 mmol). The reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was quenched withsaturated aqueous sodium bicarbonate solution. The solution was dilutedwith dichloromethane and the layers were separated. The aqueous layerwas extracted with dichloromethane and the combined organic fractionswere filtered over a plug of magnesium sulfate and concentrated. Thecrude residue was dissolved into 1 mL TFA and stirred at 80° C. for 20minutes. The reaction mixture was then cooled to room temperature,concentrated, and basified by adding aqueous NaHCO₃ solution. The crudematerial was directly purified by a silica gel column to afford thedesired product (6 mg, 65%) as a racemic mixture. The product was thenseparated with chiral HPLC using a chiral column (Phenomenex Lux 5 umCellulose-1, 21.2×250 mm) and 30% EtOH in hexanes (20 mL/min) solventsystem. Peak 1 was isolated, and further purified using preparativeLC/MS (pH=2, acetonitrile/water with TFA) to give the desired product asa TFA salt. LC-MS calculated for C₂₈H₂₅FN₉O (M+H)⁺: m/z=522.2; found522.2.

Example 111.3-(8-amino-2-((2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,Peak 2

This compound was prepared using the same procedure as described forExample 110. The product was then separated with chiral HPLC using achiral column (Phenomenex Lux 5 um Cellulose-1, 21.2×250 mm) and 30%EtOH in hexanes (20 mL/min) solvent system. Peak 2 was isolated, andfurther purified using preparative LC/MS (pH=2, acetonitrile/water withTFA) to give the desired product as a TFA salt. LC-MS calculated forC₂₈H₂₅FN₉O (M+H)⁺: m/z=522.2; found 522.2.

Example 112.3-(8-amino-2-(2-fluoro-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.075 g, 0.118 mmol) (from Example 99, step 4),1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole(0.071 g, 0.235 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.018 g, 0.024 mmol) in dioxane (1.0 mL) and water (0.2 mL) wasadded potassium phosphate tribasic (0.075 g, 0.353 mmol). The reactionmixture was stirred at 100° C. for 1 h. The reaction mixture was thendiluted with water and dichloromethane. The layers were separated andthe aqueous layer extracted with dichloromethane. The combined organicfractions were concentrated under vacuum. The resulting material wasdissolved in TFA (2 mL), and stirred at 80° C. for 20 minutes. Thereaction mixture was then cooled to room temperature, diluted with DMF(3 ml) and purified using preparative LC/MS (pH=2, acetonitrile/waterwith TFA) to give the desired product as a TFA salt. LC-MS calculatedfor C₂₅H₂₁F₂N₅O₂S (M+H)⁺: m/z=535.1; found 535.1.

Example 113.3-(8-amino-2-((2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1:6-bromo-N,N-bis(4-methoxybenzyl)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

To a solution of1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (1.00 g, 1.55 mmol) (from Example 99,step 2) and acryloyl chloride (0.253 ml, 3.10 mmol) in DMF (4 ml) anddichloromethane (4 ml) at 0° C. was added triethylamine (0.540 ml, 3.88mmol). The reaction mixture was stirred at 0° C. for for 2 hours. Thesolvent was removed under reduced pressure and the crude residue waspurified by automatic flash column chromatography to afford the desiredproduct (0.268 g, 36%). LC-MS calculated for C₂₃H₂₃BrN₅O₂ (M+H)⁺:m/z=480.1; found 480.1.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of6-bromo-N,N-bis(4-methoxybenzyl)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(0.070 g, 0.146 mmol), (3-cyano-2-fluorophenyl)boronic acid (0.048 g,0.291 mmol), cesium carbonate (0.142 g, 0.437 mmol) in dioxane (1.3 ml)and water (0.15 ml) was added tetrakis(triphenylphosphine)palladium(0)(0.034 g, 0.029 mmol). The reaction mixture was sparged with nitrogengas for five minutes, sealed and heated to 90° C. for 4 hours. Thereaction mixture was cooled to room temperature, the solvent removedunder reduced pressure, and the crude residue purified by automaticflash column chromatography to afford the desired product (0.061 g,80%). LC-MS calculated for C₃₀H₂₆FN₆O₂(M+H)⁺: m/z=521.2; found 521.1.

Step 3:3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-vinyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.287 g, 0.551 mmol), THF (2.5 ml), water (2.5 ml), sodium periodate(0.531 g, 2.481 mmol), and osmium tetroxide solution (0.433 ml, 4% inwater). The mixture was stirred at room temperature overnight. Thereaction mixture was adsorbed onto silica gel, and the solvent wasremoved under reduced pressure. The crude material (adsorbed onto silicagel) was purified by automatic flash column chromatography to afford theproduct (0.127 g, 44%). LC-MS calculated for C₂₉H₂₄FN₆O₃(M+H)⁺:m/z=523.2; found 523.1.

Step 4: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2-chloro-6-fluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of 1-chloro-3-fluoro-2-iodobenzene (0.491 g, 1.92 mmol) intetrahydrofuran (2.5 mL), isopropylmagnesium chloride lithium chloride(1.47 ml, 1.3 M solution) was added at −10° C., and the resultingmixture was stirred for 1 hour before a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-formyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.143 g, 0.274 mmol) in THF (2.5 mL) was added at −10° C. The reactionmixture was stirred for 60 min, then quenched with ammonium chloridesolution (3 mL), and extracted with dichloromethane. The combinedorganic layers were concentrated under vacuum. The crude material wasdirectly purified by a silica gel column to afford the desired product(116 mg, 65%) as a racemic mixture. LC-MS calculated for C₃₅H₂₈ClF₂N₆O₃(M+H)⁺: m/z=653.2; found 653.1.

Step 5: 3-(8-(bis(4-methoxybenzyl)amino)-2-((2-fluoro-6-vinylphenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-((2-chloro-6-fluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.194 g, 0.297 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.093 g, 0.602 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.016 g, 0.021 mmol) in dioxane (1.8 mL) and water (0.2 mL) wasadded potassium phosphate tribasic (0.170 g, 0.803 mmol). The reactionmixture was stirred at 100; C for 1 hour. The reaction mixture was thendiluted with water and DCM. The layers were separated, the aqueous layerwas extracted with DCM, and the combined organic fractions were driedover MgSO₄, filtered and concentrated. The crude material was directlypurified by a silica gel column to afford the desired product (0.097 mg,75%). LC-MS calculated for C₃₇H₃₁F₂N₆O₃(M+H)⁺: m/z=645.2; found 645.3.

Step 6: 3-(8-(bis(4-methoxybenzyl)amino)-2-((tert-butyldimethylsilyloxy)(2-fluoro-6-vinylphenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-((2-fluoro-6-vinylphenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.178 g, 0.276 mmol), DMF (2.76 ml), imidazole (0.150 g, 2.205 mmol),and TBS-C1 (0.166 g, 1.102 mmol). The reaction mixture was stirred atroom temperature for 1 hour. The solvent was removed under reducedpressure, and the crude residue was purified by automatic flash columnchromatography to afford the desired product (0.166 g, 79%). For thepurposes of characterization using LC-MS, the desired product wassubjected to deprotection of a single PMB group; an aliquot of pureproduct was dissolved into 1:1 dichloromethane/trifluoroacetic acidsolution (0.1 ml) and allowed to stand at room temperature for 5minutes, furnishing3-(2-((tert-butyldimethylsilyloxy)(2-fluoro-6-vinylphenyl)methyl)-8-(4-methoxybenzylamino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile.LC-MS calculated for C₃₅H₃₇F₂N₆O₂Si (M+H)⁺: m/z=639.3; found 639.3.

Step 7:3-(8-(bis(4-methoxybenzyl)amino)-2-((tert-butyldimethylsilyloxy)(2-fluoro-6-formylphenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A vial was charged3-(8-(bis(4-methoxybenzyl)amino)-2-(((tert-butyldimethylsilyl)oxy)(2-fluoro-6-vinylphenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.109 g, 0.144 mmol), sodium periodate (0.138 g, 0.646 mmol), THF (0.7ml), water (0.7 ml), and osmium tetroxide solution (0.113 ml, 4% inwater). The mixture was stirred at 45° C. overnight. The reactionmixture was adsorbed onto silica gel, and the solvent was removed underreduced pressure. The crude material (adsorbed onto silica gel) waspurified by automatic flash column chromatography to afford the product(0.05 g, 46%). LC-MS calculated for C₄₂H₄₃F₂N₆O₄Si (M+H)⁺: m/z=761.3;found 761.3.

Step 8:3-(8-amino-2-((2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-(((tert-butyldimethylsilyl)oxy)(2-fluoro-6-formylphenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.01 g, 0.013 mmol), hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (0.018 g,0.131 mmol), acetic acid (1.505 μl, 0.026 mmol), DCM (0.202 ml), andsodium triacetoxyborohydride (5.57 mg, 0.026 mmol). The reaction mixturewas heated to 40° C. and stirred for 2 hours. The reaction mixture wasquenched with saturated aqueous sodium bicarbonate solution and dilutedwith DCM. The layers were separated and the aqueous layer was extractedwith DCM. The combined organic fractions were concentrated, and thecrude residue was dissolved into 1 mL TFA and 0.1 ml MeOH. The solutionwas stirred at 80° C. for 20 minutes. The reaction mixture was dilutedwith DMF (4 mL) and purified by preparative LC/MS (pH=2,acetonitrile/water with TFA) to give the desired racemic product as aTFA salt. LC-MS calculated for C₂₇H₂₅F₂N₈O₂(M+H)⁺: m/z=531.2; found531.2.

Example 114.2-(4-(2-((8-amino-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide

Step 1:2-(4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorophenyl)-H-pyrazol-1-yl)aceticAcid

To a solution3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.075 g, 0.118 mmol) (from Example 99, step 4), ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate(0.157 g, 0.559 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.022 g, 0.028 mmol) in dioxane (2.0 mL) and water (0.4 mL) wasadded potassium phosphate tribasic (0.178 g, 0.838 mmol). The reactionmixture was stirred at 100° C. for 1 h. The reaction mixture was cooledto room temperature, diluted with MeOH (2 ml) and water (2 ml), and intothis solution was added lithium hydroxide hydrate (0.176 g, 4.19 mmol).The suspension was stirred at room temperature for 1 hour. Thesuspension was made neutral by addition of saturated aqueous ammoniumchloride solution, and diluted with DCM. The layers were separated andthe aqueous layer was extracted with DCM. The combined organic fractionswere dried over a plug of magnesium sulfate and concentrated.Purification by automatic flash column chromatography afforded thedesired product (0.050 g, 25%). LC-MS calculated for C₄₀H₃₃F₂N₈O₄(M+H)⁺:m/z=727.3; found 727.2.

Step 2:2-(4-(2-((8-amino-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide

A vial was charged with2-(4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)aceticacid (0.01 g, 0.014 mmol), DMF (0.46 ml), dimethylamine solution (0.069ml, 2M in THF), N,N-diisopropylethylamine (8.89 mg, 0.069 mmol), and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (10.46 mg, 0.028 mmol). The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith dichloromethane and water. The layers were separated and theaqueous layer was extracted with DCM. The combined organic fractionswere dried over a plug of magnesium sulfate and concentrated. Thecombined organic fractions were concentrated, and the crude residue wasdissolved into 1 mL TFA. The solution was stirred at 80° C. for 20minutes. The reaction mixture was diluted with DMF (4 mL) and purifiedby preparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₆H₂₂F₂N₉O (M+H)⁺:m/z=514.2; found 514.2.

Example 115.2-(4-(2-((8-amino-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)acetamide

To a solution3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.075 g, 0.118 mmol) (from Example 99, step 4),2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazol-1-yl)acetamide(0.060 g, 0.235 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.018 g, 0.024 mmol) in dioxane (1.0 mL) and water (0.2 mL) wasadded potassium phosphate tribasic (0.075 g, 0.353 mmol). The reactionmixture was stirred at 100° C. for 1 h. The reaction mixture was cooledto room temperature and diluted with water and DCM. The layers wereseparated and the aqueous layer was extracted with DCM. The combinedorganic fractions were dried over a plug of magnesium sulfate andconcentrated. The crude residue was dissolved into TFA (2 ml) andstirred at 80° C. for 20 minutes. The reaction mixture was diluted withDMF (3 mL) and purified by preparative LC/MS (pH=2, acetonitrile/waterwith TFA) to give the desired product as a TFA salt. LC-MS calculatedfor C₂₄H₁₈F₂N₉O (M+H)⁺: m/z=486.2; found 486.1.

Example 116.3-(8-amino-2-(2-fluoro-6-(1-((trans)-3-(methylamino)cyclobutyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1: Tert-butylmethyl((trans)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)carbamate

A vial was charged with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.192,0.988), tert-butyl((cis)-3-hydroxycyclobutyl)(methyl)carbamate (0.1 g,0.494 mmol), triphenylphosphine (0.285 g, 1.09 mmol), and THF (1 ml).The solution was cooled to 0° C. and diisopropyl(E)-diazene-1,2-dicarboxylate (0.234 ml, 1.19 mmol) was added dropwise.The reaction mixture was slowly warmed to room temperature and stirredovernight. The solvent was stripped and the crude residue purified byautomatic flash column chromatography to afford the desired product(0.112 g, 60%). LC-MS calculated for C₁₉H₃₃BN₃O₄(M+H)⁺: m/z=378.3; found378.3.

Step 2:3-(8-amino-2-(2-fluoro-6-(1-((trans)-3-(methylamino)cyclobutyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.01 g, 0.016 mmol) (from Example 99, step 4), tert-butylmethyl((trans)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)carbamate(0.012 g, 0.031 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.50 mg, 3.14 μmol) in dioxane (0.24 mL) and water (0.06 mL) wasadded potassium phosphate tribasic (0.010 g, 0.047 mmol). The reactionmixture was stirred at 100° C. for 1 h. The reaction mixture was cooledto room temperature and diluted with water and DCM. The layers wereseparated and the aqueous layer was extracted with DCM. The combinedorganic fractions were dried over a plug of magnesium sulfate andconcentrated. The crude residue was dissolved into TFA (1 ml) andstirred at 80° C. for 20 minutes. The reaction mixture was diluted withDMF (4 mL) and purified by preparative LC/MS (pH=2, acetonitrile/waterwith TFA) to give the desired product as a TFA salt. LC-MS calculatedfor C₂₇H₂₄F₂N₉ (M+H)⁺: m/z=512.2; found 512.1.

Example 117.3-(8-amino-2-(2-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chloro-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(0.01 g, 0.016 mmol) (from Example 99, step 4),3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile(0.008 g, 0.031 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.50 mg, 3.14 μmol) in dioxane (0.24 mL) and water (0.06 mL) wasadded potassium phosphate tribasic (0.010 g, 0.047 mmol). The reactionmixture was stirred at 100° C. for 1 hour. The reaction mixture wascooled to room temperature and diluted with water and DCM. The layerswere separated and the aqueous layer was extracted with DCM. Thecombined organic fractions were dried over a plug of magnesium sulfateand concentrated. The crude residue was dissolved into TFA (1 ml) andstirred at 80° C. for 20 minutes. The reaction mixture was diluted withDMF (4 mL) and purified by preparative LC/MS (pH=2, acetonitrile/waterwith TFA) to give the desired product as a TFA salt. LC-MS calculatedfor C₂₅H₁₈F₂N₉ (M+H)⁺: m/z=482.2; found 482.2.

Example 118.3-(8-amino-2-(2-fluoro-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A vial was charged with2-(4-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)aceticacid (0.01 g, 0.014 mmol) (from Example 114, step 1), DMF (0.46 ml),azetidin-3-ol (10 mg, 0.138 mmol), N,N-diisopropylethylamine (8.89 mg,0.069 mmol), and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (10.46 mg, 0.028 mmol). The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith dichloromethane and water. The layers were separated and theaqueous layer was extracted with DCM. The combined organic fractionswere dried over a plug of magnesium sulfate and concentrated. Thecombined organic fractions were concentrated, and the crude residue wasdissolved into 1 mL TFA. The solution was stirred at 80° C. for 20minutes. The reaction mixture was diluted with DMF (4 mL) and purifiedby preparative LC/MS (pH=2, acetonitrile/water with TFA) to give thedesired product as a TFA salt. LC-MS calculated for C₂₇H₂₂F₂N₉O₂(M+H)⁺:m/z=542.2; found 542.1.

Example 119.3-(8-amino-2-((3-methylpyridin-2-yl)methoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(bis(4-methoxybenzyl)amino)-2-hydroxy-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A reaction vial was charged with3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(50 mg, 0.090 mmol) (from Example 27, Step 4), tBuBrettPhos Pd G3 (3.8mg, 0.0045 mmol), sodium tert-butoxide (17.3 mg, 0.18 mmol), H₂O (0.1mL) and dioxane (1 mL). The reaction mixture was purged with nitrogenfor 5 min before heating to 110° C. and stirring for 5 h. The reactionmixture was then diluted with water and ethyl acetate. The organic layerwas separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The resulting residue was purified via flashchromatography to give the desired product as a white solid (40 mg,90%). LC-MS calculated for C₂₈H₂₅N₆O₃ (M+H)⁺: m/z=493.2; found 493.3.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-2-((3-methylpyridin-2-yl)methoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(Bis(4-methoxybenzyl)amino)-2-hydroxy-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(15 mg, 0.030 mmol) was dissolved in acetonitrile (0.5 mL), and2-(chloromethyl)-3-methylpyridine (13 mg, 0.090 mmol) and potassiumcarbonate (13 mg, 0.090 mmol) were added. The reaction was stirred atroom temperature for 1 h. Upon completion, NH₄Cl saturated aqueoussolution was added and the content was extracted with EtOAc (2 mL×3).The combined organic phase was dried over MgSO₄, filtered, and thesolvents removed. The crude product was re-dissolved in dichloromethane(1 mL). NBS (8 mg, 0.045 mmol) was added. The mixture was stirred at rtfor 0.5 h before quenching by the addition of aqueous Na₂SO₃ solution.The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated. The crude brominated product was added LiCl (1.3 mg, 0.030mmol), CuI (5.8 mg, 0.030 mmol), Pd₂(dba)₃ (2.3 mg, 0.003 mmol), PPh₃(1.3 mg, 0.005 mmol) and 4-(tributylstannyl)pyrimidine (14 mg, 0.038mmol). The reaction mixture was dissolved in dioxane, and purged withnitrogen for 5 min, before heating to 100° C. for 15 h. The reactionmixture was then cooled to rt, filtered, concentrated, and purified viaflash chromatography to give the desired product as a white solid (10mg, 50%). LC-MS calculated for C₃₉H₃₄N₉O₃ (M+H)⁺: m/z=676.3; found676.3.

Step 3:3-(8-amino-2-((3-methylpyridin-2-yl)methoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(bis(4-methoxybenzyl)amino)-2-((3-methylpyridin-2-yl)methoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.015 mmol) was added TFA (0.5 mL), and stirred at 100° C. for 5min. The reaction mixture was then cooled to room temperature, solventremoved, diluted with methanol, and purified via prep-LCMS (pH 2,acetonitrile/water with TFA) to give the desired product as a TFA salt.LC-MS calculated for C₂₃H₁₈N₉₀ (M+H)⁺: m/z=436.2; found 436.0.

Example 120.3-(8-Amino-2-((3-((1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1: Diethyl 2-(3-chloropyridin-2-yl)malonate

The mixture of 3-chloro-2-fluoropyridine (6.25 g, 47.5 mmol), diethylmalonate (18.27 g, 114 mmol), cesium carbonate (37.2 g, 114 mmol) andDMSO (55.9 ml) was heated at 100° C. for 10 h. The mixture was pouredonto ice, diluted with ethyl acetate. The organic layer was separated,washed with water, and brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified with silica gel column (elutingwith a gradient 0-30% ethyl acetate in hexane) to give the desiredproduct (12.9 g, 100%). LC-MS calculated for C₁₂H₁₅ClNO₄ (M+H)⁺:m/z=272.1; found 272.1.

Step 2: ethyl 2-(3-chloropyridin-2-yl)acetate

A mixture of diethyl 2-(3-chloropyridin-2-yl)malonate (12.9 g, 47.5mmol), sodium chloride (3.05 ml, 52.2 mmol), water (1.711 ml, 95 mmol)in DMSO (68 ml) was heated at 145° C. for 5 h. LCMS showed completion ofreaction. The reaction mixture was diluted with ethyl acetate and washedwith water (2×), brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified with silica gel column (eluting with a gradient0-30% ethyl acetate in hexane) to give the desired product (7.8 g, 82%).LC-MS calculated for C₉H₁₁ClNO₂ (M+H)⁺: m/z=200.0; found 200.0.

Step 3: 2-(3-chloropyridin-2-yl)acetic Acid

To a solution of ethyl 2-(3-chloropyridin-2-yl)acetate (7.8 g, 39.1mmol) in THF (130 ml) was added 1.0 M sodium hydroxide solution (78 ml,78 mmol). The resulting mixture was stirred at rt for 1 h. LCMS showedthe completion of reaction. pH of the reaction mixture was adjusted with1 N HCl to pH 3. The organic solvent was removed in vacuo. The resultingprecipitate was collected via filtration, washed with water and ethylacetate and dried under vacuum to give the product as white solid (5.5g, 82%). LC-MS calculated for C₇H₇ClNO₂ (M+H)⁺: m/z=172.0; found 172.0.

Step 4:6-Bromo-2-((3-chloropyridin-2-yl)methyl)-N,N-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

To a flask charged with 2-(3-chloropyridin-2-yl)acetic acid (0.372 g,2.168 mmol), HATU (0.907 g, 2.385 mmol) in CH2Cl2 (21.68 ml) was added1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (1.398 g, 2.168 mmol) (from Example 99,Step 2), followed by DIEA (0.757 ml, 4.34 mmol). After stirring at roomtemperature for 6 h, LCMS showed completion of reaction. The reactionmixture was diluted with DCM and water. The organic layer was washedwith brine, dried over Na2SO4, filtered and concentrated. The crude waspurified with flash chromatography (eluting with a gradient 0-40% ethylacetate in hexanes with 10% DCM) to give the desired product (1.0 g,80%). LC-MS calculated for C₂₇H₂₅BrClN₆O₂ (M+H)⁺: m/z=579.1, 581.1;found 579.1, 581.1.

Step 5:3-(8-(bis(4-methoxybenzyl)amino)-2-((3-chloropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A flask charged with6-bromo-2-((3-chloropyridin-2-yl)methyl)-N,N-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(4.70 g, 8.11 mmol), (3-cyano-2-fluorophenyl)boronic acid (1.871 g,11.35 mmol), Cs₂CO₃ (5.28 g, 16.21 mmol), tetrakis (0.937 g, 0.811mmol), 1,4-dioxane (73.7 ml) and water (7.37 ml) was evacuated undervacuum and refilled with N2 (repeated three times). The mixture washeated at 90° C. for 4 h. Another 0.3 equivalent(3-cyano-2-fluorophenyl)boronic acid (1.871 g, 11.35 mmol) was added andheated at 90° C. for 2 h. LCMS showed total completion of reaction. Thereaction mixture was diluted with DCM and water. The organic layer waswashed with brine, dried over Na2SO4, filtered and concentrated. Thecrude was triturated with hexanes and ethyl acetate, the resultingprecipitate was collected vial filtration and washed with methanol,dried under vacuum to give the desired product as white solid (4.4 g,88%). LC-MS calculated for C₃₄H₂₈ClFN₇O₂(M+H)⁺: m/z=620.2; found 620.2.

Step 6:3-(8-Amino-2-((3-((1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a vial3-(8-(bis(4-methoxybenzyl)amino)-2-((3-chloropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(15 mg, 0.024 mmol), 1-(pyridin-4-ylmethyl)-1H-pyrazol-4-amine (4.21 mg,0.024 mmol), Brettphos palladacycle (3.29 mg, 3.63 μmol), and cesiumcarbonate (12.44 μl, 0.073 mmol) were added. The vial was sealed with ateflon screw-cap, evacuated and backfilled with nitrogen (this processwas repeated a total of three times). Anhydrous t-butanol (1 ml) wasadded. The mixture was heated to 90° C. for 2 h. The reaction mixturewas filtered through a SiliaPrep-Thiol funnel, the filtrate wasconcentrated. The residue was treated with TFA (1 mL) at 80° C. for 20min. The volatile was removed, the crude was dissolved in methanol andpurified with prep-LCMS (pH 2, acetonitrile/water+TFA) to give thedesired product as TFA salt (4 mg, 33%). LC-MS calculated for C₂₇H₂₁FN₁₁(M+H)⁺: m/z=518.2; found 518.2.

Example 121.3-(8-amino-2-((3-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

The title compound was prepared using similar procedures as describedfor Example 120 with 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-aminereplacing 1-(pyridin-4-ylmethyl)-1H-pyrazol-4-amine in Step 9. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as TFA salt. LC-MScalculated for C₂₆H₂₄FN₁₀O (M+H)⁺: m/z=511.2; found 511.2.

Example 122.3-(8-Amino-2-((3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(bis(4-methoxybenzyl)amino)-2-((3-chloropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of 3-chloro-2-methylpyridine (0.367 g, 2.88 mmol) in THF(10 mL) was added 0.65 M (2,2,6,6-tetramethylpiperidin-1-yl)zinc(II)lithium chloride (6.65 ml, 4.32 mmol) at rt. The resulting yellowsolution was stirred at same temperature for 1 h, scandiumtrifluoromethanesulfonate (0.057 g, 0.115 mmol) was added and stirred atroom temperature for 15 min. A microwave vial was charge with3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.64 g, 1.152 mmol), palladium acetate (0.021 g, 0.092 mmol), and2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine(0.080 g, 0.184 mmol) was evacuated under high vacuum and backfilledwith nitrogen. The mixture was cooled to 0° C. and the zinc reagent wasadded slowly via syringe. After addition, the reaction was heated to 60°C. for 1 h. The reaction solution was partitioned between EtOAc and sat.NH₄Cl solution. The layers were separated and the aqueous extractedfurther with EtOAc (2×). The combined organics were washed with waterand brine, dried over MgSO₄, and concentrated. The resulting residue waspurified via flash chromatography to afford the product. LC-MScalculated for C₃₄H₂₉ClN₇O₂(M+H)⁺: m/z=602.2; found 602.2.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((3-chloropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-((3-chloropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.218 g, 0.362 mmol), 1-bromopyrrolidine-2,5-dione (0.061 g, 0.344mmol) and CH2Cl2 (4 ml); was stirred at 0° C. for 30 min, The reactionmixture was diluted with sat. NaHCO₃. The mixture was extracted withDCM. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified with flashchromatography to give the desired product as a light yellow oil. LC-MScalculated for C₃₄H₂₈BrClN₇O₂(M+H)⁺: m/z=680.1, 682.1; found 680.1,682.1.

Step 3:3-(8-Amino-2-((3-chloropyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((3-chloropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(86 mg, 0.126 mmol), 4-(tributylstannyl)pyrimidine (69.9 mg, 0.189mmol), and copper(I) chloride (15.00 mg, 0.152 mmol), lithium chloride(6.42 mg, 0.152 mmol) and tetrakis(triphenylphosphine)palladium(0)(14.59 mg, 0.013 mmol) in THF (3 ml) was first purged with N₂, and thenheated and stirred at 90 C for 2 h. The reaction was dilute withmethanol and purified with prep-LCMS (pH 2, acetonitrile/water with TFA)to give coupling product, that was treated with TFA (1 mL) at 80 C for20 min, The volatile was removed and the resulting residue was dissolvedin methanol and purified with prep-LCMS (pH 2, acetonitrile/water withTFA) to give the desired product. LC-MS calculated for C₂₂H₁₅ClN₉(M+H)⁺: m/z=440.1 found 440.1.

Step 4:3-(8-amino-2-((3-(1-methyl-H-pyrazol-4-yl)pyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-amino-2-((3-chloropyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(10 mg, 0.023 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.7 mg, 0.027 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (1.8 mg, 2.3 μmol) and tripotassium phosphate hydrate (11.5 mg,0.050 mmol) in 1,4-dioxane (2.0 mL)/Water (0.65 mL) was stirred at 80°C. for 1 h. The mixture was diluted in methanol and DMSO and purifiedwith prep-LCMS (pH 2, acetonitrile/water with TFA) to afford the desiredproduct as TFA salt. LCMS calculated for C₂₆H₂₀N₁₁ (M+H)⁺: 486.2 found486.2.

Example 123.(S)-3-(8-Amino-2-(2-((3-hydroxypyrrolidin-1-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A microwave vial was charge with3-(8-(bis(4-methoxybenzyl)amino)-2-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(350 mg, 0.630 mmol), palladium acetate (7.07 mg, 0.032 mmol), and2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine(27.5 mg, 0.063 mmol) was evacuated under high vacuum and backfilledwith nitrogen. (2-chlorobenzyl)zinc(II) chloride (1.4 mL, 0.693 mmol)was added via syringe. After addition, the reaction was heated to 60° C.for 1 h. The reaction solution was partitioned between EtOAc and sat.NH₄Cl solution. The layers were separated and the aqueous extractedfurther with EtOAc (2×). The combined organics were washed with waterand brine, dried over MgSO₄, and concentrated. The residue was purifiedwith flash chromatography to give the desired product (0.32 g, 82%).LC-MS calculated for C₃₅H₃₀ClN₆O₂(M+H)⁺: m/z=601.2; found 601.2.

Step 2:3-(8-(Bis(4-methoxybenzyl)amino)-5-bromo-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(0.379 g, 0.631 mmol) in DCM (6.3 ml) was add1-bromopyrrolidine-2,5-dione (0.107 g, 0.599 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 30 min. The reaction mixturewas diluted with sat. NaHCO₃. The mixture was extracted with DCM. Theorganic phase was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified with flash chromatography to givethe desired product as a light yellow oil (0.38 g, 89%). LC-MScalculated for C₃₅H₂₉BrClN₆O₂(M+H)⁺: m/z=679.1, 681.1; found 679.1,681.1.

Step 3:3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(2-chlorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(381 mg, 0.560 mmol), 4-(tributylstannyl)pyrimidine (310 mg, 0.840mmol), and copper(I) chloride (66.6 mg, 0.672 mmol), lithium chloride(28.5 mg, 0.672 mmol) and tetrakis(triphenylphosphine)palladium(0) (64.7mg, 0.056 mmol) in THF (6 ml) was first purged with N₂, and then heatedand stirred at 90° C. for 2 h. The reaction mixture was concentratedunder vacuum and the resulting residue was purified with flashchromatography to give the desired product as a light yellow oil (0.31g, 83%). LC-MS calculated for C₃₉H₃₂ClN₈O₂(M+H)⁺: m/z=679.2 found 679.2.

Step 4:3-(8-(Bis(4-methoxybenzyl)amino)-5-(pyrimidin-4-yl)-2-(2-vinylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-2-(2-chlorobenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(300 mg, 0.442 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(82 mg, 0.530 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (34.8 mg, 0.044 mmol) and tripotassium phosphate hydrate (224 mg,0.972 mmol) in 1,4-dioxane (5.0 mL)/water (1.7 mL) was stirred at 80° C.for 1 h. The reaction mixture was concentrated under vacuum and theresulting residue was purified with flash chromatography to give thedesired product as a light yellow oil. LC-MS calculated for C₄₁H₃₅N₈O₂(M+H)⁺: m/z=671.3; found 671.3.

Step 5:3-(8-(Bis(4-methoxybenzyl)amino)-2-(2-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

3-(8-(bis(4-methoxybenzyl)amino)-5-(pyrimidin-4-yl)-2-(2-vinylbenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(296 mg, 0.441 mmol) was mixed with tetrahydrofuran (2.2 mL), 0.16 Mosmium tetraoxide in water (220 μL, 0.035 mmol), sodium metaperiodate(425 mg, 1.986 mmol) and water (2.2 mL). The reaction was stirred at 60°C. for 1 h before quenched with sat. Na₂S₂O₃. The mixture was extractedwith DCM. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated to afford the product as a light yellow oil.LC-MS calculated for C₄₀H₃₃N₅O₃ (M+H)⁺: m/z=673.3; found 673.3.

Step 6:(S)-3-(8-Amino-2-(2-((3-hydroxypyrrolidin-1-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of(3-(8-(bis(4-methoxybenzyl)amino)-2-(2-formylbenzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(12 mg, 0.018 mmol), (S)-pyrrolidin-3-ol (1.6 mg, 0.018 mmol) in DCM(0.5 mL) and MeOH (0.5 mL) was added sodium triacetoxyborohydride (7.6mg, 0.036 mmol). After stirring at room temperature overnight, solventwas removed in vacuo. The residue was treated with TFA (1 mL) at 80° C.for 20 min. After removal of valotile. The residue was dissolved inmethanol and purified with preparative LCMS (pH 2, acetonitrile/waterwith TFA) to afford the desired product as TFA salt. LCMS calculated forC₂₈H₂₆N₉O (M+H)⁺: 504.2 found 504.2.

Example 124.3-(8-Amino-5-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

The title compound was prepared using similar procedures as describedfor Example 15 with6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridinereplacing (6-methoxypyridin-3-yl)boronic acid in Step 5. The reactionmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as TFA salt. LC-MS calculated for C₁₉H₁₃N₈(M+H)⁺:m/z=353.1; found 353.1.

Example 125.3-(8-amino-2-(azetidine-1-carbonyl)-5-(3-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A mixture of3-(2-(azetidine-1-carbonyl)-8-(bis(4-methoxybenzyl)amino)-5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(20 mg, 0.032 mmol) (from Example 61, Step 2),3-fluoropyridine-4-boronic acid (16 mg, 0.13 mmol), sodium carbonate (34mg, 0.32 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(5 mg, 0.006 mmol) in 4:1 dioxane/Water (1.3 mL) was stirred at 100° C.for 1.5 hours. The reaction mixture was diluted with dichloromethane andwater, and the organic solvent was concentrated in vacuo, the crudeproduct was dissolved in 3 mL TFA and stirred at 80° C. for 20 mins.After TFA being removed, the crude product was purified by preparativeLC/MS (pH=2, acetonitrile/water with TFA) to afford the desired productas a TFA salt. LC-MS calculated for C₂₁H₁₆FN₈O (M+H)⁺: m/z=415.2; found415.1.

Example 126.3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

Step 1:2-((tert-butyldimethylsilyl)oxy)-2-(2,6-difluorophenyl)acetonitrile

To a stirred solution of 2,6-difluorobenzaldehyde (0.987 ml, 8.97 mmol)in acetonitrile (9 ml) at rt was added tert-Butyldimethylsilyl cyanide(1.959 g, 13.45 mmol) (1.5 eq) and cesium fluoride (0.272 g, 1.793 mmol)(0.2 eq). The reaction mixture was stirred at rt overnight (16 h). Thereaction mixture was filtered to remove CsF. The filtrate wasconcentrated in vacuo. The residue was purified by Biotage Isolera (with40 g silica gel column) eluting with 0-10% EtOAc/Hexane to give theproduct as a colorless oil (2.468 g, 97%). LCMS calculated forC₁₄H₂₀F₂NOSi (M+H)⁺: m/z=284.1; found: 284.1.

Step 2:2-((tert-butyldimethylsilyl)oxy)-N-(3,5-dibromopyrazin-2-yl)-2-(2,6-difluorophenyl)acetimidamide

To a stirred solution of2-((tert-butyldimethylsilyl)oxy)-2-(2,6-difluorophenyl)acetonitrile (2.0g, 7.06 mmol) in anhydrous 1,2-Dichloroethane (10 ml) (5 volume) at rtwas added 3,5-dibromopyrazin-2-amine (2.73 g, 10.59 mmol) (1.5 eq) andTin(IV) chloride (1.264 ml, 10.59 mmol) (1.5 eq). The resultingsuspension was heated at 110° C. overnight (15 h). The reaction mixturewas cooled to rt. It was diluted with dichloromethane (20 mL), basifiedwith 1N NaOH to pH 10. It was extracted with dichloromethane (50 mL).The dichloromethane layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by Biotage Isolera (with120 g silica gel column) eluting with 0-30% EtOAc/Hexane to give theproduct as a light yellow solid (2.681 g, 70%). LCMS calculated forC₁₈H₂₃Br₂F₂N4OSi (M+H)⁺: m/z=534.9; found: 534.9.

Step 3: 6,8-dibromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazine

To a stirred solution of2-((tert-butyldimethylsilyl)oxy)-N-(3,5-dibromopyrazin-2-yl)-2-(2,6-difluorophenyl)acetimidamide(1.0 g, 1.831 mmol) in Hexafluoroisopropanol (18 ml) (HFIPA, 18 volume)at rt was added (Bis(trifluoroacetoxy)iodo)benzene (1.623 g, 3.66 mmol)(2 eq) and Triethylamine (1.023 ml, 7.32 mmol) (4 eq). The reactionmixture was stirred at rt for 2 hours. The reaction was quenched withsaturated aqueous NaHCO₃ (20 mL). It was extracted with dichloromethane(50 mL). Dichloromethane layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue purified by Biotage Isolera (with 120g silica gel column) eluting with 0-20% EtOAc/Hexane to give the productas a viscous light yellow oil (0.98 g, 95%). LCMS calculated forC₁₈H₂₁Br₂F₂N₄OSi (M+H)⁺: m/z=533.0; found 532.8.

Step 4: 6-bromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-N,N-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

To a stirred solution of6,8-dibromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazine(0.98 g, 1.741 mmol) in 2-Propanol (10 ml) at rt was addedbis(4-methoxybenzyl)amine (0.594 g, 2.264 mmol) andN,N-Diisopropylethylamine (0.613 ml, 3.48 mmol). The reaction mixturewas heated at 80° C. for 2 hours. The reaction mixture was cooled to rt,and concentrated in vacuo. The residue was purified by Biotage Isolera(with 120 g silica gel column) eluting with 0-30% EtOAc/Hexane to givethe product as a white foamy solid (1.190 g, 96%). LCMS calculated forC₃₄H₃₉BrF₂N₅O₃Si: m/z=710.2, found 710.3.

Step 5:3-(8-(bis(4-methoxybenzyl)amino)-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a stirred solution of6-bromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-N,N-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(1.37 g, 1.93 mmol) in 1,4-dioxane/H2O (4:1, 13 mL),(3-cyano-2-fluorophenyl)boronic acid (0.413 g, 2.5 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(78 mg, 0.1 mmol) (XPhos Pd G2) and sodium carbonate (0.613 mg, 5.78mmol) were added at rt. The reaction mixture was heated at 90° C. for 2hours. The reaction mixture was cooled to rt, extracted withdichloromethane and concentrated in vacuo. The residue was purified byBiotage Isolera eluting with 0-30% EtOAc/Hexane to give the product as afoamy solid (1.3 g, 90%). LCMS calculated for C₄₁H₄₂F₃N₆O₃Si: m/z=751.3,found 751.2.

Step 6:3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[₁,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

To a solution of3-(8-(bis(4-methoxybenzyl)amino)-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(690 mg, 0.92 mmol) in 5 mL dichloromethane,1-bromopyrrolidine-2,5-dione (180 mg, 1.0 mmol) was added at rt Thereaction mixture was stirred for overnight before it was purified byBiotage Isolera eluting with 0-30% EtOAc/Hexane to give the product as afoamy solid (700 mg, 92%). LCMS calculated for C₄₁H₄₁BrF₃N₆O₃Si:m/z=829.2, found 829.3.

Step 7: 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile

A mixture of3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-(((tert-butyldimethylsilyl)oxy)(2,6-difluorophenyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile(350 mg, 0.42 mmol), (2,6-dimethylpyridin-4-yl)boronic acid (96 mg, 0.63mmol), sodium carbonate (134 mg, 1.26 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(16 mg, 0.02 mmol) in 4:1 dioxane/Water (5 mL) was stirred at 90° C. for75 mins. The reaction mixture was diluted with dichloromethane and waterand the organic solvent was removed in vacuo, the crude product wasdissolved in 10 mL TFA and stirred at 80° C. for 1 hour. After TFA beingremoved in vacuo, the crude product was basified by sodium bicarbonatesolution, and extracted with dichloromethane. The dichloromethane layerwas concentrated in vacuo, and purified by Biotage Isolera to give thedesired product as a racemic mixture (140 mg, 66%) The product was thenseparated with chiral HPLC using a chiral column (Phenomenex Lux 5 umCellulose-4, 21.2×250 mm) and 75% EtOH in hexanes (20 mL/min) solventsystem. Peak 2 was isolated, and further purified by preparative LC/MS(pH=2, acetonitrile/water with TFA) to give the desired product as a TFAsalt. LC-MS calculated for C₂₆H₁₉F₃N₇O (M+H)⁺: m/z=502.2; found 502.2.

Example 127.3-(8-amino-5-(1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1: 6-bromo-2-(methyl-d3)pyridazin-3(2H)-one

To a solution of 6-bromopyridazin-3(2H)-one (1.1 g, 6.3 mmol) in 9 mLDMF, iodomethane-d3 (1.0 g, 6.91 mmol) and potassium carbonate (1.3 g,9.4 mmol) were added at rt and stirred overnight. The resulting mixturewas quenched with ammonium chloride solution and extracted withdichloromethane, after concentrated in vacuo, the crude product waspurified by Biotage Isolera to afford the desired product (0.96 g, 80%)as white solid. LC-MS calculated for C₅H₃D₃BrN₂O (M+H)⁺: m/z=192.0;found 192.1.

Step 2:2-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one

To a mixture of 6-bromo-2-(methyl-d3)pyridazin-3(2H)-one (300 mg, 1.56mmol), potassium acetate (460 mg, 4.69 mmol), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (440 mg, 1.7mmol) in dioxane (5 mL), Tetrakis(triphenylphosphine)palladium(0) (90mg, 0.08 mmol) was added at rt, the resulting mixture was stirred at100° C. overnight. The reaction mixture was then quenched with ammoniumchloride solution and extracted with dichloromethane, after beingconcentrated in vacuo, the crude product was purified by Biotage Isoler,and the desired product (0.17 g, 46%) was obtained as a white solid.LC-MS calculated for C₁₁H₁₅D₃BN₂O₃(M+H)⁺: m/z=240.2; found 240.2.

Step 3:3-(8-amino-5-(1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a mixture of3-(8-amino-5-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(Example 27, Step 7; 20 mg, 0.05 mmol),2-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (24 mg, 0.1 mmol), and sodium carbonate (20 mg, 0.2 mmol) indioxane/water (4:1, 1.5 mL),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4 mg, 0.005 mmol) (XPhos Pd G2) was added. The resulting mixture washeated at 90° C. for 1 hour. The mixture was concentrated and purifiedby preparative LCMS (pH 2, acetonitrile/water with TFA) to afford thedesired product as TFA salt. LCMS calculated for C₂₃H₁₅D₃N₉O (M+H)⁺:m/z=439.2; found 439.2.

Example 128.3-(8-amino-2-((6-methoxypyridin-2-yl)methyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

Step 1:6-bromo-N,N-bis(4-methoxybenzyl)-2-((6-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine

To a vial charged with 2-(6-methoxypyridin-2-yl)acetic acid (47 mg, 0.28mmol), HATU (133 mg, 0.35 mmol) in dichloromethane 2 mL was added1,2-diamino-3-(bis(4-methoxybenzyl)amino)-5-bromopyrazin-1-ium2,4,6-trimethylbenzenesulfonate (example 99, step 2, 150 mg, 0.23 mmol),followed by N-ethyl-N-isopropylpropan-2-amine (90 mg, 0.7 mmol). Afterstirring at room temperature for 6 hours, the reaction mixture wasdiluted with dichloromethane and water. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crude waspurified with flash chromatography (eluting with a gradient 0-10% ethylacetate in dichloromethane) to give the desired product (100 mg, 75%).LC-MS calculated for C₂₈H₂₈BrN₆O₂(M+H)⁺: m/z=575.1, 577.1; found 575.1,577.1.

Step 2:3-(8-(bis(4-methoxybenzyl)amino)-2-((6-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

To a solution of6-bromo-N,N-bis(4-methoxybenzyl)-2-((6-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine(75 mg, 0.13 mmol) and (3-cyanophenyl)boronic acid (29 mg, 0.2 mmol) in2 mL 1,4-dioxane/H₂O=4:1, sodium carbonate (42 mg, 0.4 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(3 mg, 0.004 mmol) (XPhos Pd G2) were added. The reaction mixture washeated to 90° C. and stirred for 1 hour before being diluted withdichloromethane and water. The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude was purifiedwith flash chromatography (eluting with a gradient 0-10% ethyl acetatein dichloromethane) to give the desired product (60 mg, 77%). LC-MScalculated for C₃₅H₃₂N₇O₃ (M+H)⁺: m/z=598.2; found 598.2.

Step 3:3-(8-amino-5-(1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile

A solution of3-(8-(bis(4-methoxybenzyl)amino)-2-((6-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile(60 mg, 0.1 mmol) in 4 mL TFA was heated to 80° C. and stirred for 20mins. The reaction mixture was then concentrated in vacuo, basified withsodium bicarbonate solution and extracted with dichloromethane. Theorganic layer was concentrated to get crude product for next step. To asolution of above product in 3 mL dichloromethane,1-bromopyrrolidine-2,5-dione (23 mg, 0.13 mmol) was added at rt and thereaction mixture was stirred for overnight before being concentrated invacuo. The crude product was then used for next step directly withoutany further purification.

To a solution of the above crude product in dioxane/water (4:1, 2.0 mL),2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one(35 mg, 1.5 mmol), sodium carbonate (30 mg, 0.3 mmol)chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4 mg, 0.005 mmol) (XPhos Pd G2) was added. The resulting mixture washeated at 90° C. for 1 hour before being diluted with acetonitrile andmethanol and purified by preparative LCMS (pH 2, acetonitrile/water withTFA) to afford the desired product as TFA salt. LCMS calculated forC₂₄H₂₀N₉O₂ (M+H)⁺: m/z=466.2; found 466.2.

Example A. Adenosine A2A Receptor Cyclic AMP GS Assay

Stably transfected HEK-293 cells expressing the human adenosine A2Areceptor (Perkin Elmer) are maintained in MEM culture medium with 10%FBS and 400 μg/mL Geneticin (Life Technologies). 18 to 24 hours prior toassay, geneticin is removed from culture. The cisbio cAMP-GS Dynamic kitutilizing the FRET (Fluorescence Resonance Energy Transfer) technologyis used to measure cAMP accumulation in the cells. Compounds of thepresent disclosure at an appropriate concentration are mixed with 10000cells/well in white 96 well half area plates (Perkin Elmer) for 30 minat rt gently shaking. Agonist, CGS21680 (R&D Technologies) at 4 nM isadded to each well for 60 min at room temperature gently shaking.Detection reagents, d2-labeled cAMP (acceptor) and anti-cAMP cryptate(donor) are added to each well for 60 min at room temperature gentlyshaking. Plates are read on Pherastar (BMG Labtech), fluorescence ratio665/620 is calculated and EC₅₀ determination is performed by fitting thecurve of percent of control versus the log of the compound concentrationusing GraphPad Prism.

Example B. Adenosine A2B Receptor Cyclic AMP GS Assay

Stably transfected HEK-293 cells expressing the human adenosine A2Breceptor (Perkin Elmer) were maintained in MEM culture medium with 10%FBS and 100 μg/mL Geneticin (Life Technologies). 18 to 24 hours prior toassay, geneticin was removed from culture. The cisbio cAMP-GS Dynamickit utilizing the FRET (Fluorescence Resonance Energy Transfer)technology was used to measure cAMP accumulation in the cells. Compoundsof the present disclosure at an appropriate concentration were mixedwith 10000 cells/well in white 96 well half area plates (Perkin Elmer)for 30 min at room temperature gently shaking. Agonist, NECA (R&DTechnologies) at 12 nM was added to each well for 60 min at roomtemperature gently shaking. Detection reagents, d2-labeled cAMP(acceptor) and anti-cAMP cryptate (donor) were added to each well for 60min at rt gently shaking. Plates were read on Pherastar (BMG Labtech),fluorescence ratio 665/620 was calculated and EC₅₀ determination wasperformed by fitting the curve of percent of control versus the log ofthe compound concentration using GraphPad Prism. The EC₅₀ data for theExamples obtained via this method are shown in Table 1.

Example C. A2A Tag-Lite® HTRF Assay

Assays were conducted in black low volume 384-well polystyrene plates(Greiner 784076-25) in a final volume of 10 μL. Test compounds werefirst serially diluted in DMSO and 100 nl added to the plate wellsbefore the addition of other reaction components. The finalconcentration of DMSO was 1%. Tag-Lite® Adenosine A2A labeled cells(CisBio C1TT1A2A) were diluted 1:5 into Tag-lite buffer (CisBio LABMED)and spun 1200 g for 5 mins. The pellet was resuspended at a volume 10.4×the initial cell suspension volume in Tag-lite buffer, and Adenosine A2AReceptor Red antagonist fluorescent ligand (CisBio L0058RED) added at12.5 nM final concentration. 10 ul of the cell and ligand mix was addedto the assay wells and incubated at room temperature for 45 minutesbefore reading on a PHERAstar FS plate reader (BMG Labtech) with HTRF337/620/665 optical module. Percent binding of the fluorescent ligandwas calculated; where 100 nM of A2A antagonist control ZM 241385 (Tocris1036) displaces the ligand 100% and 1% DMSO has 0% displacement. The %binding data versus the log of the inhibitor concentration was fitted toa one-site competitive binding model (GraphPad Prism version 7.02) wherethe ligand constant=12.5 nM and the ligand Kd=1.85 nM. The K_(i) datafor the Examples obtained via this method are shown in Table 1.

Example D. A2B Filter Binding Assay

Assays are conducted in deep well polypropylene plates (Greiner 786201)in a final volume of 550 μL. Test compounds are first serially dilutedin DMSO and 5.5 ul is then added to the plate wells before the additionof other reaction components. The final concentration of DMSO is 3%.HEK293 cell membranes overexpressing the human adenosine receptor A2B(Perkin Elmer ES-113-M400UA) are diluted to 40 μg/mL in 50 mM HEPES pH7.0, 5 mM MgCl₂, 1 mM EDTA (Assay buffer).[3H]8-cyclopentyl-1,3-dipropylxanthine (Perkin Elmer NET974001MC) isdiluted in assay buffer+22% DMSO to 24.2 nM, and then further diluted to1 nM by addition to the diluted membranes. 545 μl of the membrane andligand mix is added to the assay wells and incubated on a shaker at roomtemperature for 1 hour. The membrane mix is then filtered over aUniFilter GF/C filter plate (Perkin Elmer 6005174) pre-soaked in 50 mMHEPES pH 6.5, 5 mM MgCl₂, 1 mM EDTA 0.5% BSA and then washed with 5 mLice cold 50 mM HEPES pH 6.5, 5 mM MgCl₂, 1 mM EDTA 0.2% BSA. 50 μlMicroScint™ cocktail (Perkin Elmer 6013621) is added and plates are readon a Topcount NXT FS (Perkin Elmer). Percent binding of the [3H]ligandis calculated, where 1000 nM of LUF 5834 (Tocris 4603) control displacesthe ligand 100% and 3% DMSO has 0% displacement. The % binding dataversus the log of the inhibitor concentration is fitted to a one-sitecompetitive binding model (GraphPad Prism version 7.02) where the ligandconstant=2 nM and the ligand Kd=13 nM.

Example E. A1 and A3 SPA Binding Assays

Both assays are conducted in white 384-well polystyrene plates (Greiner781075) in a final volume of 50 μL. Inhibitors are first seriallydiluted in DMSO and 100 nL is added to the plate wells before theaddition of other reaction components. The final concentration of DMSOis 2%.

Wheatgerm agglutinin-coated yttrium silicate SPA beads (Perkin ElmerRPNQ0023) and CHO-K1 cell membranes overexpressing each human adeonsinereceptor are incubated in 50 mM HEPES pH 7.0, 5 mM MgCl₂, 1 mM EDTA(Assay buffer) on a rotary stirrer for 2 hours at 4° C. The beads arepelleted by centrifugation at 6000 g for one minute, and then thesupernatant with unbound membrane is discarded. The beads arere-suspended to the original volume in assay buffer. Each radioligand isdiluted in assay buffer+22% DMSO at 12.2× the final concentration, andthen added to the SPA bead suspension. 50 μl of the SPA bead reactionmix is added to the assay wells and the plates shaken at 600 rpm for 1hour at room temperature. The beads are then allowed to settle for 1hour before reading on a Topcount NXT FS (Perkin Elmer). Percent bindingof the radiolabeled ligand is calculated, where a control at >100× Kidisplaces the ligand 100% and 2% DMSO has 0% displacement. The % bindingdata versus the log of the inhibitor concentration is fitted to aone-site competitive binding model (GraphPad Prism version 7.02). Assayconditions are provided in Table A below.

TABLE A Assay Component A1 A3 SPA beads 3 mg/mL 1.25 mg/mL in Hepesbuffer Membrane 60 μg/mL 20 μg/mL Perkin Elmer Perkin Elemer ES-010ES-012 Radioligand 1 nM [3 H] DP-CPX 0.1 nM [125I] MECA (Perkin Elmer(Perkin Elmer NET974) NEX312) K_(D) = 1 nM K_(D) = 0.8 nM Control 1 μMDPCPX 0.1 μM IB-MECA (Tocris 0439) (Tocris 1066)

The A_(2A)_Ki data and A_(2B)_cAMP_EC₅₀ data are provided below. Thesymbol “†” indicates A_(2A)_Ki or A_(2B)_cAMP_EC₅₀≤10 nM, “††” indicatesA_(2A)_Ki or A_(2B)_cAMP_EC₅₀>10 nM but≤100 nM. “†††” indicatesA_(2A)_Ki or A_(2B)_cAMP_EC₅₀>100 nM but≤1 μM; and “††††” indicatesA_(2A)_Ki or A_(2B)_cAMP_EC₅₀ is greater than 1 μM.

TABLE 1 Ex. A_(2A)_Ki A_(2B)_cAMP_EC₅₀ No. (nM) (nM)   1 † ††   2 † ††  3 † †††   4 † ††   5 † †††   6 †† ††††   7 † †   8 † ††   9 † ††  10 ††  11 † †  12 † ††  13 †† †††  14 †† ††††  15 † †  16 † †  17 † †  18 ††  19 † ††  20 † †  21 † †††  22 † †††  23 † †  24 † ††  25 † ††  26 †††  27 † †  28 † ††  29 † †  30 † ††  31 † ††  32 † †  33 † †  34 † †† 35 † †  36 † †  37 † †  38 † †  39 † †  40 † †  41 † †  42 † †  43 † † 44 † †  45 † †  46 † †  47 † ††  48 † ††  49 † †  50 † †  51 † †  52 ††  53 † †  54 † †  55 † †  56 † †  57 † †  58 † †  59 † ††  60 † ††  61† †  62 † †  63 † †  64 † †  65 † ††  66 † †  67 † †  68 † ††  69 † † 70 † ††  71 † †  72 † †  73 † †  74 † †  75 † †  76 † ††  77 † †  78 ††  79 † †  80 † †  81 † †  82 † †  83 † †  84 † †  85 † ††  86 † †  87 †††  88 † ††  89 † ††  90 † †††  91 † ††  92 † †  93 † †  94 † ††  95 †††  96 † ††  97 † †  98 † †  99 † †† 100 † ††† 101 † † 102 † † 103 † †104 † †† 105 † † 106 † † 107 † †† 108 † † 109 † † 110 † ††† 111 † † 112† † 113 † †† 114 † †† 115 † † 116 † †† 117 † † 118 † † 119 † † 120 † ††121 † †† 122 † †† 123 † †† 124 † † 125 † †† 126 † †† 127 † † 128 † ††

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein: Cy¹ is selectedfrom C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy¹ areeach optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R⁷ substituents; each R⁷ is independently selected from D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a7), SR^(a7), NHOR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)NR^(c7)(OR^(a7)), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7),C(═NR^(e7))R^(b7), C(═NOH)R^(b7), C(═NCN)R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NOH)NR^(c7)R^(d7), NR^(c7)C(═NCN)NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))R^(b7), NR^(c7)S(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)(═NR^(e7))R^(b7),NR^(c7)S(O)NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),S(O)₂NR^(c7)R^(d7), OS(O)(═NR^(e7))R^(b7), OS(O)₂R^(b7), SF₅,P(O)R^(f7)R^(g7), OP(O)(OR^(h7))(OR^(i7)), P(O)(OR^(h7))(OR^(i7)), andBR^(j7)R^(k7), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁷ are each optionally substituted with1, 2, 3, or 4 independently selected R^(7A) substituents; each R^(a7),R^(b7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a7), R^(b7), R^(c7) and R^(d7) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(7A) substituents; or, any R^(c7) and R^(d7), attached to the same Natom, together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group, wherein the 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(7A) substituents; each R^(e7) is independentlyselected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(f7) and R^(g7) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(h7) and R^(i7) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(j7) and R^(k7) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy; or any R^(j7) and R^(k7) attached to thesame B atom, together with the B atom to which they are attached, form a5- or 6-membered heterocycloalkyl group optionally substituted with 1,2, 3, or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(7A) is independently selected from OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₅ cycloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino,C₁₋₆ alkylcarbonyloxy, aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy,di(C₁₋₆ alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl,C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; R² isselected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a2), SR^(a2), NHOR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2)C(═NR^(e2))R^(b2), C(═NOH)R^(b2), C(═NCN)R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NOH)NR^(c2)R^(d2), NR^(c2)C(═NCN)NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅,P(O)R^(f2)R^(g2), OP(O)(OR^(h2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), andBR^(j2)R^(k2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(2A) substituents; R⁴ isselected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NOH)R^(b4), C(═NCN)R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NOH)NR^(c4)R^(d4), NR^(c4)C(═NCN)NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)(═NR^(e4))R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), SF₅,P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), andBR^(j4)R^(k4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(4A) substituents; providedthat: (a) when R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl and 4-10 membered heterocycloalkyl, wherein theC₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, 3, 4,5, or 6 independently selected R^(2A) substituents; then R⁴ is selectedfrom H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NOH)R^(b4)), C(═NCN)R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NOH)NR^(c4)R^(d4), NR^(c4)C(═NCN)NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)(═NR^(e4))R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), SF₅,P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), andBR^(j4)R^(k4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(4A) substituents; or,alternatively, (b) when R² is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a2), SR^(a2),NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2)), C(═NOH)R^(b2),C(═NCN)R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NOH)NR^(c2)R^(d2),NR^(c2)C(═NCN)NR^(c2)R^(d2), NR^(c2) (═NR^(e2))R^(b2),NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅, P(O)R^(f2)R^(g2),OP(O)(OR^(h2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), and BR^(j2)R^(k2),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, 4, 5, or 6 independently selectedR^(2A) substituents; then R⁴ is selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NOH)R^(b4),C(═NCN)R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NOH)NR^(c4)R^(d4),NR^(c4)C(═NCN)NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), SF₅, P(O)R^(f4)R^(g4),OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are eachoptionally substituted with 1, 2, 3, 4, 5, or 6 independently selectedR^(4A) substituents; each R^(a2), R^(b2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a2), R^(b2),R^(c2) and R^(d2) are each optionally substituted with 1, 2, 3, 4, 5, or6 independently selected R^(2A) substituents; or, any R^(c2) and R^(d2),attached to the same N atom, together with the N atom to which they areattached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, or 6 independently selected R^(2A) substituents; each R^(e2) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(f2)and R^(g2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(h2) and R′² is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(j2) and R^(k2) is independentlyselected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or any R^(j2) andR^(k2) attached to the same B atom, together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(2A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a21),SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NOH)R^(b21), C(═NCN)R^(b21),C(═NR^(e21))NR^(c21)R^(d21), NR^(c21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NOH)NR^(c21)R^(d21), NR^(c21)C(═NCN)NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))R^(b21), NR^(c12)S(O)NR^(c21)R^(d21),NR^(c21)S(O)R^(b21)NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)(═NR^(e21))R^(b21),NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21), OS(O)(═NR^(e21))R^(b21),OS(O)₂R^(b21), SF₅, P(O)R^(f21)R^(g21), OP(O)(OR^(h21))(OR^(i21)),P(O)(OR^(h21))(OR^(i21)), and BR^(j21)R^(k21), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents; each R^(a21), R^(b21), R^(c21) and R^(d21) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21),R^(c21) and R^(d21) are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents; or, any R^(c21) and R^(d21),attached to the same N atom, together with the N atom to which they areattached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(2B) substituents; each R^(e21) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(f21)and R^(g21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(h21) and R^(i21) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(j21) and R^(k21) is independentlyselected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or any R^(j21) andR^(k21) attached to the same B atom, together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(2B) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a22),SR^(a22), NHOR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22),C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NOH)R^(b22), C(═NCN)R^(b22),C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NOH)NR^(c22)R^(d22), NR^(c22)C(═NCN)R^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)S(O)NR^(c22)R^(d22),NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), OS(O)₂R^(b22), SF₅, P(O)R^(d22)R^(g22),OP(O)(OR^(h22))(OR^(i22)), P(O)(OR^(h22))(OR^(i22)), andBR^(i22)R^(k22), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2C) substituents; eachR^(a22), R^(b22), R^(c22) and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(b22),R^(c22) and R^(d22) are each optionally substituted with 1, 2, 3, or 4independently selected R^(2C) substituents; or, any R^(c22) and R^(d22),attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group,wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(2C)substituents; each R^(e22) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each R^(f22) and R^(g22) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(h22) andR^(i22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(j22) andR^(k22) is independently selected from OH, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy; or any R^(j22) and R^(k22) attached to the same B atom,together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(2C) is independently selected from OH, NO₂, CN, halo,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁-3alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy,alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino; each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(b4),R^(c4) and R^(d4) are each optionally substituted with 1, 2, 3, 4, 5, or6 independently selected R^(4A) substituents; or, any R^(c4) and R^(d4),attached to the same N atom, together with the N atom to which they areattached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, or 6 independently selected R^(4A) substituents; each R^(e4) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(f4)and R^(g4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(h4) and R^(i4) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(j4) and R^(k4) is independentlyselected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or any R^(j4) andR^(k4) attached to the same B atom, together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(4A) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a41),SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NOH)R^(b41), C(═NCN)R^(b41),C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NOH)NR^(c41)R^(d41), NR^(c41)C(═NCN)NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))R^(b41), NR^(c41)S(O)NR^(c41)R^(d41),NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), OS(O)₂R^(b41), SF₅, P(O)R^(f41)R^(g41),OP(O)(OR^(h41))(OR^(i41)), P(O)(OR^(h41))(OR^(i41)), andBR^(j41)R^(k41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are each optionally substitutedwith 1, 2, 3, 4, 5, or 6 independently selected R^(4B) substituents;each R^(a41), R^(b41), R^(c41) and R^(d41) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(b41),R^(c41) and R^(d41) are each optionally substituted with 1, 2, 3, 4, 5,or 6 independently selected R^(4B) substituents; or, any R^(c41) andR^(d41), attached to the same N atom, together with the N atom to whichthey are attached, form a 4-10 membered heterocycloalkyl group, whereinthe 4-10 membered heterocycloalkyl group is optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(4B) substituents; eachR^(e41) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;each R^(f41) and R^(g41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(h41) and R^(i41) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(j41) and R^(k41) is independentlyselected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or any R^(j41) andR^(k41) attached to the same B atom, together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(4B) isindependently selected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a42),SR^(a42), NHOR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),C(═NR^(e42))R^(b42), C(═NOH)R^(b42), C(═NCN)R^(b42),C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NOH)NR^(c42)R^(d42), NR^(c42)C(═NCN)NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))R^(b42), NR^(c42)S(O)NR^(c42)R^(d42),NR^(c42)S(O)R^(b42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), OS(O)₂R^(b42), SF₅, P(O)R^(f42)R^(g42),OP(O)(OR^(h42))(OR^(i42)), P(O)(OR^(h42))(OR^(i42)), andBR^(j42)R^(k42), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents; eachR^(a42), R^(b42), R^(c42) and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(b42),R^(c42) and R^(d42) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4C) substituents; or, any R^(e42) and R^(d42),attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group,wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(4C)substituents; each R^(e42) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each R^(f42) and R^(g42) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(h42) andR^(i42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(j42) andR^(k42) is independently selected from OH, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy; or any R^(j42) and R^(k42) attached to the same B atom,together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(4C) is independently selected from D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a43), SR^(a43), NHOR^(a43), C(O)R^(b43),C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)), C(O)OR^(a43), OC(O)R^(b43),OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43), NR^(c43)NR^(c43)R^(d43),NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43), NR^(c43)C(O)NR^(c43)R^(d43),C(═NR^(e43))R^(b43), C(═NOH)R^(b43), C(═NCN)R^(b43),C(═NR^(e43))NR^(c43)R^(d43), NR^(c43), C(═NR^(e43))NR^(c43)R^(d43),NR^(c43)C(═NOH)NR^(c43)R^(d43), NR^(c43)C(═NCN)NR^(c43)R^(d43),NR^(c43)C(═NR^(e43))R^(b43), NR^(c43)S(O)NR^(c43)R^(d43),NR^(c43)S(O)R^(b43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)(═NR^(e43))R^(b43), NR^(c43)S(O)₂NR^(c43)R^(d43),S(O)R^(b43), S(O)NR^(c43)R^(d43), S(O)₂R^(b43) S(O)₂NR^(c43)R^(d43),OS(O)(═NR^(e43))R^(b43), OS(O)₂R^(b43), SF₅, P(O)R^(f43)R^(g43),OP(O)(OR^(h43))(OR^(i43)), P(O)(OR^(h43))(OR^(i143)), andBR^(j43)R^(k43), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4D) substituents; eachR^(a43), R^(b43), R^(c43) and R^(d43) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a43), R^(b43),R^(c43) and R^(d43) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents; or, any R^(c43) and R^(d43),attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group,wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(4D)substituents; each R^(e43) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each R^(f43) and R^(g43) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(h43) andR^(i43) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(j43) andR^(k43) is independently selected from OH, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy; or any R^(j43) and R^(k43) attached to the same B atom,together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(4D) is independently selected from D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a44), SR^(a44), NHOR^(a44), C(O)R^(b44),C(O)NR^(c44)R^(d44), (O)NR^(c44)(OR^(a44)), C(O)OR^(a44), OC(O)R^(b44),OC(O)NR^(c44)R^(d44), NR^(c44)R^(d44), NR^(c44)NR^(c44)R^(d44),NR^(c44)C(O)R^(b44), NR^(c44)C(O)OR^(a44), NR^(c44)C(O)NR^(c44)R^(d44),C(═NR^(e44))R^(b44), C(═NOH)R^(b44), C(═NCN)R^(b44),C(═NR^(e44))NR^(c44)R^(d44), NR^(c44)C(═NR^(e44))NR^(c44)R^(d44),NR^(c44)C(═NOH)NR^(c44)R^(d44), NR^(c44)C(═NCN)NR^(c44)R^(d44),NR^(c44)C(═NR^(e44))R^(b44), NR^(c44)S(O)NR^(c44)R^(d44),NR^(c44)S(O)R^(b44), NR^(c44)S(O)₂R^(b44),NR^(c44)S(O)(═NR^(e44))R^(b44), NR^(c44)S(O)₂NR^(c44)R^(d44),S(O)R^(b44), S(O)NR^(c44)R^(d44), S(O)₂R^(b44), S(O)₂NR^(c44)R^(d44),OS(O)(═NR^(e44))R^(b44), OS(O)₂R^(b44), SF₅, P(O)R^(f44)R^(g44),OP(O)(OR^(h44))(OR^(i44)), P(O)(OR^(h44))(OR^(i44)), andBR^(j44)R^(k44), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-7 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4D) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4E) substituents; eachR^(a44), R^(b44), R^(c44) and R^(d44) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a44), R^(b44), R^(c44) and R^(d44) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4E) substituents; or, anyR^(c44) and R^(d44), attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4E) substituents; each R^(e44) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(f44)and R^(g44) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(h44) and R^(i44) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-7 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-7 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(j44) and R^(k44) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy; or any R^(j44) and R^(k44) attached to thesame B atom, together with the B atom to which they are attached, form a5- or 6-membered heterocycloalkyl group optionally substituted with 1,2, 3, or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and each R^(4E) is independently selected from OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy,alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, amino sulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein 1, 2, 3, 4, 5, 6, 7,or 8 hydrogen atoms, attached to carbon atoms of any alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl substituentsor —C₁₋₆ alkyl-, alkylene, alkenylene, and alkynylene linking groups,are each optionally replaced by a deuterium atom. 3.-23. (canceled) 24.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy¹ is phenyl which is substituted by 1 or 2 independentlyselected R⁷ substituents; and each R⁷ is independently selected fromhalo and CN.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is cyanophenyl.
 26. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy¹ is3-cyanophenyl or 3-cyano-2-fluorophenyl.
 27. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R² is selected fromC₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; each R^(2A) is independently selected from D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), C(O)OR^(b21),C(O)NR^(c21)R^(d21), C(O))R^(a21), OC(O) R^(b21), OC(O)NR^(c21)R^(d21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21),NR^(c21)C(O)NR^(c21)R^(d21), S(O)R^(b21), and S(O)₂R^(b21), wherein saidC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R^(2A) are each optionally substituted by 1, 2, or 3independently selected R^(2B) substitutents; each R^(a21), R²⁴¹,R^(c21), and R^(d21) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl of R^(a21), R²⁴¹, R^(c21), andR^(d21) is optionally substituted by 1, 2, or 3 independently selectedR^(2A) substituents; and each R^(2B) is independently selected from D,halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.
 28. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R² isselected from 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl, wherein the 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl of R² are each optionally substituted with 1, 2, or 3independently selected R^(2A) substituents; each R^(2A) is independentlyselected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and OH, wherein saidC₁₋₆ alkyl of R^(2A) is optionally substituted by 1, 2, or 3independently selected R^(2B) substitutents; and each R^(2B) isindependently selected from D, halo, and OH.
 29. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R² is selectedfrom 6-oxo-1,6-dihydropyridin-3-yl, pyrimidin-4-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, 4-methyloxazol-5-yl,4-ethyloxazol-5-yl, 3-methylpyridin-4-yl,difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl,2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl,1-ethyl-1H-pyrazol-5-yl, 6-hydroxypyridin-3-yl,2,6-dimethylpyridin-4-yl, 3-methyl-1H-pyrazol-4-yl,[1,2,4]triazolo[4,3-a]pyridin-6-yl, oxazol-5-yl,imidazo[1,2-a]pyridine-6-yl, 3-fluoropyridin-4-yl, and1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl.
 30. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R² is H. 31.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is 6-oxo-1,6-dihydropyridin-3-yl orimidazo[1,2-a]pyridin-6-yl; and R⁴ is H.
 32. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R² is H; and R⁴ is—NHC(O)OC₁₋₆ alkyl.
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: R⁴ is selected from C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, OR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4),S(O)₂NR^(c4)R^(d4), and S(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are eachoptionally substituted with 1, 2, or 3 independently selected R^(4A)substituents; each R^(a4), R^(b4), R^(c4), and R^(d4) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a4),R^(b4), R^(c4) and R^(d4) are each optionally substituted with 1, 2, or3 independently selected R^(4A) substituents; each R^(4A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, OR^(a41), (O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), NR^(c41)R^(d41),S(O)₂NR^(c41)R^(d41), and S(O)₂R^(b41), wherein the C₁₋₆ alkyl, 5 C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are each optionally substitutedwith 1, 2, or 3 independently selected R^(4B) substituents; eachR^(a41), R^(b41), R^(c41) and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(a41), R^(b41), R^(c41) and R^(d41) are each optionallysubstituted with 1, 2, or 3 independently selected R^(4B) substituents;each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆ cycloalkyl)-C₁₋₃ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), NR^(c42)R^(d42)S(O)₂NR^(c42)R^(d42), and S(O)₂R^(b42),wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆cycloalkyl)-C₁₋₃ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-,(5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionallysubstituted with 1, 2, or 3 independently selected R^(4C) substituents;each R^(a42), R^(b42), R^(c42) and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6membered heteroaryl of R^(a42), R^(b42), R^(c42) and R^(d42) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4C)substituents; each R^(4C) is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, CN, OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43),C(O)OR^(a43), NR^(c43)R^(d43), S(O)₂NR^(c43)R^(d43), and S(O)₂R^(b43),wherein the C₁₋₆ alkyl of R^(4C) is optionally substituted with 1 or 2independently selected R^(4D) substituents; each R^(a43), R^(b43),R^(c43) and R^(d43) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl of R^(a43), R^(b43), R^(c43) andR^(d43) are each optionally substituted with 1 or 2 independentlyselected R^(4D) substituents; or, any R^(c43) and R^(d43), attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, or 6-membered heterocycloalkyl group, wherein the 4-, 5-,or 6-membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(4D) substituents; and each R^(4D)is independently selected from C₁₋₃ alkyl and OH.
 34. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ isselected from phenyl-C₁₋₃ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₃alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-, OR^(a4), C(O)R^(b4), andS(O)₂R^(b4), wherein the phenyl-C₁₋₃ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₃ alkyl- and (5-10 membered heteroaryl)-C₁₋₃ alkyl-of R⁴ are each optionally substituted with 1, 2, or 3 independentlyselected R^(4A) substituents; each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from phenyl, 4-7 membered heterocycloalkyl, and(5-6 membered heteroaryl)-C₁₋₃ alkyl-, wherein the phenyl, 4-7 memberedheterocycloalkyl, and (5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(a4),R^(b4), R^(c4) and R^(d4) are each optionally substituted with 1, 2, or3 independently selected R^(4A) substituents; each R^(4A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-6membered heteroaryl, (4-10 membered heterocycloalkyl)-C₁₋₃ alkyl-,OR^(a41), S(O)₂R^(b41), and NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, 5-6membered heteroaryl, and (4-10 membered heterocycloalkyl)-C₁₋₃ alkyl- ofR^(4A) are each optionally substituted with 1, 2, or 3 independentlyselected R^(4B) substituents; each R^(a41), R^(b41), R^(c41) and R^(d41)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 5-6membered heteroaryl, wherein the C₁₋₆ alkyl and 5-6 membered heteroarylof R^(a41), R^(b41), R^(c41) and R^(d41) are each optionally substitutedwith 1, 2, or 3 independently selected R^(4B) substituents; each R^(4B)is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)OR^(a42), andNR^(c42)R^(d42), wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionally substituted with1, 2, or 3 independently selected R^(4C) substituents; each R^(a42),R^(b42), R^(c42) and R^(d42) is independently selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 5-7 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 5-7 membered heterocycloalkyl of R^(a42), R^(b42),R^(c42) and R^(d42) are each optionally substituted with 1, 2, or 3independently selected R^(4C) substituents; each R^(4C) is independentlyselected from C₁₋₆ alkyl, CN, C(O)NR^(c43)R^(d43), C(O)OR^(a43),NR^(c43)R^(d43) and S(O)₂R^(b43), wherein the C₁₋₆ alkyl of R^(4C) isoptionally substituted with 1 or 2 independently selected R^(4D)substituents; each R^(a43), R^(b43), R^(c43) and R^(d43) isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, whereinthe C₁₋₆ alkyl of R^(a43), R^(b43), R^(c43) and R^(d43) are eachoptionally substituted with 1 or 2 independently selected R^(4D)substituents; or, any R^(c43) and R^(d43), attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, or6-membered heterocycloalkyl group, wherein the 4-, 5-, or 6-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents; each R^(4D) is independentlyselected from C₁₋₃ alkyl and OH.
 35. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is selected frompyridin-2-ylmethyl, 1H-Pyrrolo[2,3-b]pyridin-1-yl,7H-pyrrolo[2,3-b]pyridin-7-yl, 2-fluorophenoxy,hydroxy(pyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl,(imidazo[1,2-a]pyridin-8-yl)methyl, (pyrazolo[1,5-a]pyridin-7-yl)methyl,(2H-indazol-2-yl)methyl, (1H-indazol-1-yl)methyl,(2,6-difluorophenyl)(hydroxy)methyl,(2,5-difluorophenyl)(hydroxy)methyl,(2,3-difluorophenyl)(hydroxy)methyl, (2-fluorophenyl)(hydroxy)methyl,(2-chlorophenyl)(hydroxy)methyl, hydroxy(phenyl)methyl, phenylsulfonyl,azetidine-1-carbonyl, benzo[d]oxazol-4-ylmethyl,2-fluoro-6-(1-methyl-1H-pyrazol-5-yl)benzyl,2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl,2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)benzyl,2-fluoro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl,2-fluoro-6-((3-oxopiperazin-1-yl)methyl)benzyl,2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl,2-fluoro-6-(((2-methyl-2H-1,2,3-triazol-4-yl)amino)methyl)benzyl,2-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl,amino(2,6-difluorophenyl)methyl,(2,6-difluorophenyl)(methylamino)methyl,(2,6-difluorophenyl)((2-hydroxyethyl)amino)methyl,amino(2-fluorophenyl)methyl, amino(2,6-difluorophenyl)methyl,(3-(oxazol-5-yl)pyridin-2-yl)methyl,2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)benzyl,(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-yl)methyl,2-((1-acetylpiperidin-4-yl)methyl)-6-fluorobenzyl,(2-(difluoromethoxy)-6-fluorophenyl)(hydroxy)methyl,2-fluoro-6-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)benzyl,(2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl,2-fluoro-6-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)benzyl,(2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl,2-fluoro-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)benzyl,2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)(hydroxy)methyl,2-fluoro-6-(1-((trans)-3-(methylamino)cyclobutyl)-1H-pyrazol-4-yl)benzyl,2-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-6-fluorobenzyl,2-fluoro-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)benzyl,(3-methylpyridin-2-yl)methoxy,(3-((1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl,(3-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl,(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl,2-((3-hydroxypyrrolidin-1-yl)methyl)benzyl, and(6-methoxypyridin-2-yl)methyl.
 36. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: Cy¹ is phenyl whichis substituted by 1 or 2 independently selected R⁷ substituents; each R⁷is independently selected from halo and CN; R² is selected from H, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; each R^(2A) is independently selected from D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), (O)R^(b21), (O)NR^(c21)R^(d21),C(O)OR^(a21), OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),S(O)R^(b21), and S(O)₂R^(b21), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(2A) are eachoptionally substituted by 1, 2, or 3 independently selected R^(2B)substitutents; each R^(a21), R²⁴¹, R^(c21), and R^(d21) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkylof R^(a21), R²⁴¹, R^(c21), and R^(d21) is optionally substituted by 1,2, or 3 independently selected R^(2A) substituents; each R^(2B) isindependently selected from D, halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,C₁₋₄ alkyl, C₁₋₄ haloalkyl, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino; R⁴ is selected from C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), S(O)₂NR^(c4)R^(d4), andS(O)₂R^(b4), wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, or 3 independently selected R^(4A) substituents; each R^(a4),R^(b4), and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(a4), R^(b4), R^(c4) and R^(d4) are each optionallysubstituted with 1, 2, or 3 independently selected R^(4A) substituents;each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)R^(a41), NR^(c41)R^(d41), S(O)₂NR^(c41)R^(d41),and S(O)₂R^(b41), wherein the C₁₋₆ alkyl, 5 C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(4A) are each optionally substituted with 1, 2, or 3independently selected R^(4B) substituents; each R^(a41), R^(b41),R^(c41) and R^(d41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and5-6 membered heteroaryl, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroarylof R^(a41), R^(b41), R^(c41) and R^(d41) are each optionally substitutedwith 1, 2, or 3 independently selected R^(4B) substituents; each R^(4B)is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl,C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,phenyl-C₁₋₃ alkyl-, (C₃₋₆ cycloalkyl)-C₁₋₃ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₃ alkyl-, (5-6 membered heteroaryl)-C₁₋₃ alkyl-,CN, OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42),NR^(c42)R^(d42), S(O)₂NR^(c42)R^(d42), and S(O)₂R^(b42), wherein theC₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, phenyl-C₁₋₃ alkyl-, (C₃₋₆ cycloalkyl)-C₁₋₃ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₃ alkyl-, (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionally substituted with1, 2, or 3 independently selected R^(4C) substituents; each R^(a42),R^(b42), R^(c42) and R^(d42) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(a42), R^(b42), R^(c42) and R^(d42) are each optionallysubstituted with 1, 2, or 3 independently selected R^(4C) substituents;each R^(4C) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)OR^(a43),NR^(c43)R^(d43), S(O)₂NR^(c43)R^(d43), and S(O)₂R^(b43), wherein theC₁₋₆ alkyl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4C) are each optionally substituted with 1or 2 independently selected R^(4D) substituents; each R^(a43), R^(b43),R^(c43) and R^(d43) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl of R^(a43), R^(b43), R^(c43) andR^(d43) are each optionally substituted with 1 or 2 independentlyselected R^(4D) substituents; or, any R^(c43) and R^(d43), attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, or 6-membered heterocycloalkyl group, wherein the 4-, 5-,or 6-membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(4D) substituents; and each R^(4D)is independently selected from C₁₋₃ alkyl and OH.
 37. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein: Cy¹ is3-cyanophenyl or 3-cyano-2-fluorophenyl; R² is selected from H, 5-10membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the 5-10membered heteroaryl and 4-7 membered heterocycloalkyl of R² are eachoptionally substituted with 1, 2, or 3 independently selected R^(2A)substituents; each R^(2A) is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, and OH, wherein said C₁₋₆ alkyl of R^(2A) isoptionally substituted by 1, 2, or 3 independently selected R^(2B)substitutents; each R^(2B) is independently selected from D, halo, andOH; R⁴ is selected from phenyl-C₁₋₃ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₃ alkyl-, (5-10 membered heteroaryl)-C₁₋₃ alkyl-,OR^(a4), C(O)R^(b4), and S(O)₂R^(b4), wherein the phenyl-C₁₋₃ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₃ alkyl- and (5-10 memberedheteroaryl)-C₁₋₃ alkyl- of R⁴ are each optionally substituted with 1, 2,or 3 independently selected R^(4A) substituents; each R^(a4), R^(b4),R^(c4), and R^(d4) is independently selected from phenyl, 4-7 memberedheterocycloalkyl, and (5-6 membered heteroaryl)-C₁₋₃ alkyl-, wherein thephenyl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(a4), R^(b4), R^(c4) and R^(d4) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4A)substituents; each R^(4A) is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, 5-6 membered heteroaryl, (4-10 memberedheterocycloalkyl)-C₁₋₃ alkyl-, OR^(a41), S(O)₂R^(b41), andNR^(c41)R^(d41), wherein the C₁₋₆ alkyl, 5-6 membered heteroaryl, and(4-10 membered heterocycloalkyl)-C₁₋₃ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents; each R^(a41), R^(b41), R^(c41) and R^(d41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 5-6membered heteroaryl, wherein the C₁₋₆ alkyl and 5-6 membered heteroarylof R^(a41), R^(b41), R^(c41) and R^(d41) are each optionally substitutedwith 1, 2, or 3 independently selected R^(4B) substituents; each R^(4B)is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, (5-6 memberedheteroaryl)-C₁₋₃ alkyl-, CN, OR^(a42), C(O)R^(b42), C(O)OR^(a42), andNR^(c42)R^(d42), wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, and (5-6 memberedheteroaryl)-C₁₋₃ alkyl- of R^(4B) are each optionally substituted with1, 2, or 3 independently selected R^(4C) substituents; each R^(a42),R^(b42), R^(c42) and R^(d42) is independently selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 5-7 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 5-7 membered heterocycloalkyl of R^(a42), R^(b42),R^(c42) and R^(d42) are each optionally substituted with 1, 2, or 3independently selected R^(4C) substituents; each R^(4C) is independentlyselected from C₁₋₆ alkyl, CN, C(O)NR^(c43)R^(d43), C(O)OR^(a43),NR^(c43)R^(d43) and S(O)₂R^(b43), wherein the C₁₋₆ alkyl, 4-7 memberedheterocycloalkyl, and (5-6 membered heteroaryl)-C₁₋₃ alkyl- of R^(4C)are each optionally substituted with 1 or 2 independently selectedR^(4D) substituents; each R^(a43), R^(b43), R^(c43) and R^(d43) isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, whereinthe C₁₋₆ alkyl of R^(a43), R^(b43), R^(c43) and R^(d43) are eachoptionally substituted with 1 or 2 independently selected R^(4D)substituents; or, any R^(c43) and R^(d43), attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, or6-membered heterocycloalkyl group, wherein the 4-, 5-, or 6-memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4D) substituents; and each R^(4D) isindependently selected from C₁₋₃ alkyl and OH.
 38. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: R² isselected from 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl,wherein the 5-6 membered heteroaryl and 4-6 membered heterocycloalkylare each optionally substituted with 1 or 2 C₁₋₃ alkyl groups; R⁴ isphenyl-C₁₋₃ alkyl- or pyridyl-C₁₋₃ alkyl-, wherein the phenyl-C₁₋₃alkyl- and pyridyl-C₁₋₃ alkyl- are each optionally substituted with 1,2, or 3 substituents independently selected from OH and halo; and Cy¹ iscyanophenyl.
 39. The compound of claim 1, which is a compound of Formula(IIIb):

or a pharmaceutically acceptable salt thereof, wherein n is an integerfrom 0 to
 4. 40. The compound of claim 1, which is a compound of Formula(IIIc):

or a pharmaceutically acceptable salt thereof.
 41. The compound of claim1, selected from:Ethyl(8-amino-6-(3-cyanophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)carbamate;3-(8-Amino-5-(6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(pyridin-2-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(S)-1-(2-((8-Amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)pyrrolidine-3-carboxylicacid;1-(2-((8-Amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)azetidine-3-carboxylicacid;3-(2-((1H-Pyrrolo[2,3-b]pyridin-1-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(2-((7H-pyrrolo[2,3-b]pyridin-7-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(2-fluorophenoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(hydroxy(pyridin-2-yl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-5-(4-ethyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-5-(3-methylpyridin-4-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(imidazo[1,2-c]pyridin-8-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(pyrazolo[1,5-c]pyridin-7-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(242H-Indazol-2-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(2-((1H-Indazol-1-yl)methyl)-8-amino-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-((2,5-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-((2,3-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-((2-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-((2-chlorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(hydroxy(phenyl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(phenylsulfonyl)-5-(pyrimidin-4-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-(azetidine-1-carbonyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-amino-5-(6-hydroxypyridin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(benzo[d]oxazol-4-ylmethyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-(1-methyl-1H-pyrazol-5-yl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(R)-1-(2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)-3-methylpyrrolidine-3-carboxylicacid;3-(8-amino-2-(2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(S)-3-(8-amino-2-(2-fluoro-6-((2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;2-((2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)amino)acetamide;3-(8-amino-2-(2-fluoro-6-((3-oxopiperazin-1-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(1S,3S)-3-((2-((8-amino-6-(3-cyanophenyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)amino)cyclobutane-1-carboxylicacid;3-(8-amino-2-(2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-(((2-methyl-2H-1,2,3-triazol-4-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(S)-3-(8-amino-2-(2-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(R)-1-(2-((8-amino-6-(3-cyanophenyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)-3-fluorobenzyl)-3-methylpyrrolidine-3-carboxylicacid;3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(methylamino)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2,6-difluorophenyl)((2-hydroxyethyl)amino)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(amino(2-fluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((3-(oxazol-5-yl)pyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;(S)-3-(8-amino-2-(2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-(2-fluoro-6-((6-methyl-5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-5-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-5-(4-(2,2-difluoro-1-hydroxyethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-5-(2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(2-(2-((1-acetylpiperidin-4-yl)methyl)-6-fluorobenzyl)-8-amino-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(1-ethyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2-(difluoromethoxy)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((2-((dimethylamino)methyl)-6-fluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(oxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2-fluoro-6-(pyrrolidin-1-ylmethyl)phenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(2-fluoro-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((2-fluoro-6-((6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;2-(4-(2-((8-amino-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;2-(4-(2-((8-amino-6-(3-cyano-2-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrazin-2-yl)methyl)-3-fluorophenyl)-1H-pyrazol-1-yl)acetamide;3-(8-amino-2-(2-fluoro-6-(1-((trans)-3-(methylamino)cyclobutyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-(2-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-(2-fluoro-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((3-methylpyridin-2-yl)methoxy)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-2-((3-((1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-2-((3-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-Amino-2-((3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;(S)-3-(8-Amino-2-(2-((3-hydroxypyrrolidin-1-yl)methyl)benzyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-Amino-5-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-(azetidine-1-carbonyl)-5-(3-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-fluorobenzonitrile;3-(8-amino-5-(1-(methyl-d3)-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile;and3-(8-amino-2-((6-methoxypyridin-2-yl)methyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,or a pharmaceutically acceptable salt thereof.
 42. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier.
 43. A method of inhibiting an activity of an adenosinereceptor, comprising contacting the receptor with a compound of claim 1,or a pharmaceutically acceptable salt thereof.
 44. A method of treatinga disease or disorder in a patient, wherein the disease or disorder isassociated with abnormal expression of A2A or A2B receptors, comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 45.The method of claim 44, wherein the disease or disorder is cancer, aninflammatory disease, a cardiovascular disease, or a neurodegenerativedisease.
 46. The method of claim 45, wherein the cancer is bladdercancer, lung cancer, melanoma, breast cancer, cervical cancer, ovariancancer, colorectal cancer, pancreatic cancer, esophageal cancer,prostate cancer, kidney cancer, skin cancer, thyroid cancer, livercancer, uterine cancer, head and neck cancer, or renal cell carcinoma.47. The method of claim 45, wherein the cancer is non-small cell lungcancer (NSCLC), metastatic castrate-resistant prostate carcinoma(mCRPC), or colorectal carcinoma (CRC).
 48. The method of claim 45,wherein the inflammatory disease is pulmonary inflammation.
 49. Themethod of claim 48, wherein the pulmonary inflammation isbleomycin-induced pulmonary fibrosis.
 50. The method of claim 45,wherein the inflammatory disease is an adenosine receptor dependentallergic reaction or adenosine receptor immune reaction.
 51. The methodof claim 50, wherein the adenosine receptor dependent allergic reactionis A2B receptor dependent.
 52. The method of claim 45, wherein theinflammatory disease is a respiratory disorder, sepsis, reperfusioninjury, or thrombosis.
 53. The method of claim 45, wherein thecardiovascular disease is coronary artery disease, cerebrovasculardisease, peripheral artery disease, aortic atherosclerosis, or aneurysm.54. The method of claim 53, wherein the coronary artery disease ismyocardial infarction, angina pectoris, or heart failure.
 55. The methodof claim 53, wherein the cerebrovascular disease is stroke or transientischemic attack.
 56. The method of claim 45, wherein theneurodegenerative disease is Parkinson's disease.
 57. The method ofclaim 44, wherein the disease or disorder is diabetes or insulinresistance.
 58. A method of treating or preventing atheroscleroticplaque formation in a patient in need thereof, comprising administeringto said patient a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.